KR20100121629A - Compounds comprising a cyclobutoxy group - Google Patents

Abstract

The present invention provides a compound of formula (I) comprising a cyclobutoxy group, a process for preparing the same, and a pharmaceutical composition comprising the compound. And their use as medicaments:

Description

Compound containing cyclobutoxy group {COMPOUNDS COMPRISING A CYCLOBUTOXY GROUP}

The present invention relates to compounds comprising cyclobutoxy groups, methods for their preparation, pharmaceutical compositions comprising said compounds, and their use as medicaments.

Histamine H ₃ receptors were known many years ago and in 1983 Aran, J.M. (Arrang JM) et al. Pharmacologically confirmed in Nature (1983, 302, 832-837). Since the cloning of human histamine H ₃ receptors in 1999, histamine H ₃ receptors have been successfully cloned by sequence homology from various species, including rats, guinea pigs, mice and monkeys.

Histamine H ₃ receptor agonists, antagonists and inverse agonists are described, for example, in Stark, H. (Exp. Opin. Ther. Patents 2003, 13, 851-865), and Ruth R. (Stark, H.). It has been demonstrated as an effective therapeutic as described by Natures Drug Discovery 2005, 4, 107-120 by Leurs R., et al.

Histamine H ₃ receptors are predominantly expressed in the central nervous system of mammals but can also be found in the autonomic nervous system. It has been demonstrated that histamine H ₃ receptors exhibit high constitutive activity, which activity is manifested in the absence of endogenous histamine or H ₃ receptor agonists. Thus, histamine H ₃ receptor antagonists and / or inverse agonists could inhibit this activity.

General pharmacology of histamine H ₃ receptor, including H ₃ receptor subtypes are described (Life Sci. 2003, 73, 3043-3072) in Hancock, A. A. (Hancock, AA). These histamine H ₃ receptors are regarded not only as exhibiting synapses for histamine functional neurons but also as heterologous receptors for non-histamine functional neurons (Barnes, W. et al., Eur. J. Pharmacol. 2001, 431 , 215-221). Indeed, histamine H ₃ receptors have been demonstrated to modulate the release of histamine and other important neurotransmitters such as acetylcholine, dopamine, serotonin, norepinephrine and γ-aminobutyric acid (GABA).

Thus, histamine H ₃ receptors are currently attracting attention for the development of new therapeutic agents, and the literature indicates that the new histamine H ₃ receptor antagonists or inverse agonists are mild cognitive impairment (MCI), Alzheimer's disease, learning and memory disorders, cognitive impairment, attention Deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), Parkinson's disease, schizophrenia, dementia, depression, epilepsy, seizures or convulsions, sleep-wake disorders, lethargic seizures, pain and / or obesity It is proposed that it may be useful for treating and preventing a disease or condition.

H ₃ receptor ligands are in Morissette, S. Cholinergic-deficiency disorders, mild cognitive impairment and Alzheimer's disease, either alone or in combination with acetylcholinesterase inhibitors, as described by Morisset, S. et al. (Eur. J. Pharmacol. 1996, 315, R1-R2). It may be useful for the treatment of the disease.

H ₃ receptor ligands are Macleod, al. As described by McLeod, R. (J. Pharmacol. Exp. Ther. 2003, 305, 1037-1044), either alone or in combination with histamine H ₁ receptor antagonists may be useful in the treatment of upper respiratory allergic disorders. have.

H ₃ receptor ligands alone or in combination with serotonin reuptake inhibitors. second. M. It may be useful for the treatment of depression, as described by Keith, JM et al. (Bioorg. Med. Chem. Lett. 2007, 17, 702-706).

As described in international patent application WO 02/072093, H ₃ receptor ligands are used alone or in combination with muscarinic receptor ligands and especially muscarinic M ₂ -receptor antagonists to treat cognitive impairment, Alzheimer's disease, attention deficit hyperactivity disorder. It may be useful for treatment.

H ₃ receptor ligands are also found in Passani, M. According to Passani, MB et al. (Trends Pharmacol. Sci. 2004, 25 (12), 618-625), it would be useful for the treatment of sleep / wake disorders and arousal / boundary disorders such as hypersleep and narcolepsy. Can be.

In general, H ₃ receptor ligands and in particular H ₃ receptor antagonists or inverse agonists are Hancock, A. a. And Fox, G. B. (Hancock, AA and Fox, GB), as reviewed in Expert Opin. Invest. Drugs 2004, 13, 1237-1248.

In particular, histamine H ₃ receptor antagonists or inverse agonists are used to treat cognitive dysfunction in diseases such as mild cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, Down's syndrome, as well as in the treatment of attention deficit hyperactivity disorder (ADHD). May be useful as a non-psychotic. Witkin, JM et al., Pharmacol. Ther. 2004, 103 (1), 1-20].

H ₃ receptor antagonists or inverse agonists may be useful in the treatment of psychosis, such as schizophrenia, migraine, eating disorders such as obesity, inflammation, pain, anxiety, stress, depression, cardiovascular disease, especially acute myocardial infarction.

Therefore, there is a need to prepare new compounds that can effectively function as H ₃ receptor ligands.

Early literature reports (eg, Ali, SM et al., J. Med. Chem. 1999, 42, 903-909 and Stark, H. et al., Drugs Fut. 1996, 21, 507-520) It describes that imidazole functional groups are essential for high affinity histamine H ₃ receptor ligands; This is, for example, US patent applications US 6,506,756 B2, US 6,518,287 B2, US 6,528,522 B2 and US 6,762,186 B2, for example, regarding H ₃ receptor antagonists or substituted imidazole compounds having dual histamine H ₁ receptor and H ₃ receptor antagonist activity. Was confirmed by.

International patent application WO 02/12214 relates to non-imidazole aryloxyalkylamines for the treatment of diseases and conditions mediated by histamine receptors.

International patent application WO 02/074758 relates to bicyclic heterocyclic derivatives containing amine moieties and recorded as H ₃ receptor ligands.

International patent application WO 01/748810 relates to an H ₃ receptor antagonist comprising a benzoxazole or benzothiazole moiety.

International patent application WO 2006/103045 describes compounds comprising an oxazole or thiazole moiety as the H ₃ receptor ligand.

International patent application WO 2006/136924 describes a class of phenoxycyclobutyl derivatives as H ₃ receptor antagonists.

US patent application US 2005/171181 discloses cyclobutyl-arylamines as H ₃ receptor modulators.

International patent application WO2006 / 097691 describes fused thiazole derivatives exhibiting histamine H ₃ receptor antagonist activity.

International patent applications WO 2006/132914 and WO 2007/038074 describe cyclobutyl amine derivatives as H ₃ receptor modulators.

It has surprisingly been discovered that compounds of formula (I) can act as H ₃ receptor ligands and thus exhibit therapeutic properties for one or more of the pathologies mentioned below.

The present invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is a substituted or unsubstituted aliphatic or cyclic amino group linked to a cyclobutyl group via amino nitrogen;

A ¹ is CH, C-halogen or N;

B is selected from the group consisting of heteroaryl, 5-8 membered heterocycloalkyl and 5-8 membered cycloalkyl;

X is O, S, NH or N (C _{1 -4} alkyl);

Y is O, S or NH;

R ¹ is sulfonyl, amino, substituted or non-unsubstituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, unsubstituted or unsubstituted C _{2 -6-alkynyl,} optionally substituted aryl, which is unsubstituted or heteroaryl, optionally substituted non-substituted C _{3 -8} cycloalkyl, substituted or non-3- to 8-membered heterocycloalkyl, acyl, optionally substituted non-substituted C _{1 -6} alkyl, aryl, optionally substituted that is not C _{1 -6-alkyl-heteroaryl,} substituted or unsubstituted C _{2 -6} alkenyl aryl, substituted or unsubstituted C _{2 -6} alkenyl heteroaryl, substituted or unsubstituted C _{2 -6-alkynyl} aryl, optionally substituted C _{2 -6-alkynyl} heteroaryl, optionally substituted C _{1 -6} alkyl, cycloalkyl, are optionally substituted C _{1 -6} alkyl, heterocycloalkyl, optionally substituted C _{2 -6} alkenyl cycloalkyl, optionally substituted C _{2 -6} alkenyl heterocycloalkyl, substituted or unsubstituted C _{2 -6-alkynyl} cycloalkyl, substituted or unsubstituted C _{2 -6-alkynyl} heterocycloalkyl , alkoxycarbonyl, aminocarbonyl, optionally substituted C _1-6 alkyl, carboxy, optionally substituted C _{1 -6} alkyl, acyl, substituted acyl or aryl acyl, aryl, optionally substituted heteroaryl which is unsubstituted, optionally substituted C _{3 -8} (hetero) cycloalkyl acyl, optionally substituted C _{1 -6} alkyl acyloxy, substituted or unsubstituted C _-6 alkyl, alkoxy, substituted or unsubstituted C _-6 alkyl alkoxy carbonyl, substituted or non-C _-6 alkylamino-carbonyl, optionally substituted non-substituted C _{1 -6} alkyl, acyl, acylamino, acylamino-carbonyl, urethane Also, optionally substituted C _{1 -6} alkyl ureido, substituted or unsubstituted C _{1 -6-alkyl} carbamate, unsubstituted or substituted C _{1 -6} alkylamino, optionally substituted C _1-6 alkylsulfonyloxy, optionally substituted C _{1 -6} alkyl sulfonyl, optionally substituted C _{1 -6} alkyl sulfinyl, optionally substituted C _{1 -6} alkyl sulfanyl, substituted or unsubstituted C _1-6 alkylsulfonyl, amino, aminosulfonyl, optionally substituted C _1-6 alkyl aminosulfonyl, hydroxy, substituted or unsubstituted C _1-6 alkyl, hydroxy, phosphonate, substituted or unsubstituted It is selected from C _1-6 alkyl phosphonate, an optionally substituted C _1-6 alkyl, phosphono, halogen, cyano, carboxy, oxo, the group which contains or consists of thioxo;

n is 0, 1, 2 or 3;

R ² is hydrogen, sulfonyl, amino, optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, substituted or unsubstituted C _{2 -6-alkynyl,} substituted or unsubstituted aryl, substituted or non-heteroaryl, optionally substituted non-substituted C _{3 -8} cycloalkyl, substituted or that are 3 to 8-membered heterocycloalkyl, acyl not, optionally substituted optionally substituted C _{1 -6} alkyl, aryl, substituted or unsubstituted C _{1 -6-alkyl-heteroaryl,} substituted or unsubstituted C _{2 -6} alkenyl aryl, substituted or unsubstituted C _{2 -6} alkenyl heteroaryl, substituted or unsubstituted C _{2 -6-alkynyl} aryl, optionally substituted C _{2 -6-alkynyl} heteroaryl, optionally substituted C _{1 -6} alkyl, cycloalkyl, optionally substituted C _{1 -6} alkyl heterocycloalkyl, substituted or not substituted Is C _{2 -6} alkenyl, cycloalkyl, optionally substituted C _{2 -6} alkenyl heterocycloalkyl, substituted or unsubstituted C _{2 -6-alkynyl} cycloalkyl, substituted or unsubstituted C _2-6 alkynyl, heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6} alkyl carboxy, optionally substituted C _{1 -6} alkyl, acyl, substituted or unsubstituted aryl acyl, substituted or unsubstituted heteroaryl aryl acyl, substituted or unsubstituted C _{3 -8} - (hetero) cycloalkyl acyl, that is optionally substituted with C _{1 -6-alkyl} acyloxy, substituted or unsubstituted C _{1 -6} alkyl, alkoxy, optionally substituted C _1-6 alkyl alkoxycarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} optionally substituted C _{1 -6} alkyl acylamino, acylamino, acyl aminocarboxylic Carbonyl, ureido, optionally substituted C _{1 -6} alkyl ureido, substituted or unsubstituted C _{1 -6-alkyl} carbamate, unsubstituted or substituted C _{1 -6} alkylamino, optionally substituted C _1-6 alkylsulfonyloxy, substituted or non-C1-6 alkylsulfonyl, optionally substituted non-substituted C _1-6 alkyl sulfinyl, substituted or unsubstituted C _1-6 alkylsulfanyl, optionally substituted It is C _{1 -6-alkyl} sulfonylamino, aminosulfonyl, optionally substituted C _{1 -6} alkyl, amino-sulfonyl, hydroxy, optionally substituted C _{1 -6} alkyl, hydroxy, phosphonate, substituted or unsubstituted C _{1 -6} alkyl phosphonate, optionally substituted C _{1 -6} alkyl phosphono, include halogen, cyano, carboxy, oxo, thioxo, or it is selected from the group consisting therefrom;

m is 0 or 1;

R ³ is hydrogen or C _{1 -6} alkyl or halogen or a C _{1 -6} alkoxy.

As used herein, the term "alkyl" has a linear (unbranched) or branched moiety, or a combination thereof, and has a saturation of 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Group representing a monovalent hydrocarbon radical.

"Alkyl" groups according to the invention may be substituted or unsubstituted. Preferred unsubstituted alkyl groups according to the invention are methyl, ethyl, n-propyl, isopropyl and tert-butyl. An "alkyl" group may be substituted with one or more substituents including halogen.

The term "halogen" as used herein denotes a fluorine, chlorine, bromine or iodine atom. Preferred halogen atoms according to the invention are fluorine.

As used herein, the term "hydroxy" refers to a group of the formula -OH.

As used herein, the term "C _{1 -6} alkyl, hydroxy" means the above defined alkyl substituted by one or more "hydroxy". A preferred "C _{1 -6} alkyl, hydroxy" according to the present invention group is 2,3-dihydroxy-propyl, (2S) -2,3- dihydroxy-propyl, (2R) -2,3- dihydroxy -Propyl and 2-hydroxyethyl.

As used herein, the term "C _{3 -8} cycloalkyl" is a C 3 -C 8 1 derived from a saturated or partially unsaturated cyclic hydrocarbon group represents a group. Preferred groups are C _{3 -8} cycloalkyl in accordance with the present invention, a cyclobutyl, a cyclobutenyl, and cyclopentenyl.

The C _{3 -8} cycloalkyl "hydroxy", "amino" in accordance with the present invention, may be replaced by "amino carbonyl" or "oxo". Examples of such substituted C _{3 -8} cycloalkyl in accordance with the present invention, 3-hydroxy-cyclobutyl, 1 - (aminocarbonyl) cyclopropyl, 1-hydroxy-cyclopropyl, 2-hydroxy-3,4 Dioxocyclobut-1-en-1-yl, 3,4-di-oxo-2- (propan-2-yloxy) cyclobut-1-en-1-yl and 2-amino-3,4- Dioxocyclobut-1-en-1-yl.

As used herein, the term "C _{1 -6-alkyl} cycloalkyl" refers to a C _{1 -6} alkyl having a cycloalkyl substituent as defined herein above.

The term "alkylene" as used herein refers to a group of the formula-(CH ₂ ) _x- , where x is 2 to 6, preferably 3 to 6.

The term "methylene" as used herein refers to a group of the formula -CH _2- .

The term "C _{2 -6} alkenyl" preferably means an alkenyl group having 2 to 6 carbon atoms alkenyl unsaturation positions numbered, at least one or two eggs. The term "C _{2 -6} alkynyl" preferably means an alkynyl having 2 to 6 carbon atoms numbered, at least one or two alkynyl unsaturation position.

As used herein, the term “aryl” means an unsaturated aromatic carbocyclic group having 6 to 14 carbon atoms having a single ring (eg phenyl) or multiple condensed rings (eg naphthyl). The "aryl" group may optionally be substituted with halogen, C _{1 -4} alkyl, or 1-4 substituents independently selected from C _{1 -4} alkoxy as defined herein.

As used herein, the terms used in the "C _{1 -6-alkyl} aryl" refers to C _{1 -6} alkyl group having a substituent on the aryl defined herein.

As used herein, the term “heteroaryl” refers to an aryl group as defined above herein where one or more carbon atoms is substituted with one or more heteroatoms selected from O, S or N. Preferred heteroaryls according to the invention are pyridyl and triazolyl.

The term "C _{1 -6-alkyl} heteroaryl" refers to a C _{1 -6} alkyl having a heteroaryl substituent as defined herein above.

As used herein, the term "C _{2 -6} - alkenyl aryl" refers to a C _{2 -6} alkenyl optionally substituted with aryl as defined above herein.

As used herein, the term "C _{2 -6} - alkenyl heteroaryl" refers to a C _{2 -6} alkenyl substituted with a heteroaryl, as defined herein above.

As used herein, the term "C _{2 -6} - alkynyl aryl" refers to a C _{2 -6-alkynyl} optionally substituted with aryl as defined above herein.

As used herein, the term "C _{2 -6} - alkynyl heteroaryl" refers to a C _{2 -6-alkynyl} substituted with a heteroaryl, as defined herein above.

As used herein, the term “alkoxy” refers to ^a group of the formula —OR ^a , wherein R ^a is an alkyl, carboxyalkyl or aryl group as defined herein.

As used herein, the term "C _{1 -6-alkyl} alkoxy" means a C _{1 -6} alkyl having an alkoxy substituent as defined herein above.

As used herein, the term "carbonyl" refers to a group of the formula -C (= 0)-.

As used herein, the term "acyl" of the formula -C (= O) represent a group of a R ^b, wherein R ^b is defined herein C _{1 -6} alkyl, C _{1 -6} alkyl, alkoxy, hydroxy, aminocarbonyl or is optionally substituted by oxo C _{3 -8} cycloalkyl, 3- to 8-membered heterocycloalkyl, C _{1 -6} alkyl, heterocycloalkyl, C _{1 -6} alkyl, hydroxy, C _{1 -6} alkylamino, C _{1 - 6-alkyl} acylamino, aminocarbonyl, C _{1 -6} alkylamino-carbonyl, alkoxycarbonyl, C _{1 -6} alkyl ureido is a heteroaryl radicals. Preferred acyl groups according to the invention are acetyl, methoxyacetyl, aminoacetyl, hydroxyacetyl, 3-amino-3-oxopropanoyl, 3,3,3-trifluoropropanoyl, (5-methyl-2H -1,2,3-triazol-4-yl) carbonyl, 4- (1-oxidodothiomorpholin-4-yl) butanoyl, 3- (acetylamino) propanoyl, (carboxymethoxy) Acetyl, 3,3,3-trifluoro-2-hydroxypropanoyl, tetrahydro-2H-pyran-4-ylcarbonyl, (1-hydroxycyclopropyl) carbonyl, [(1-aminocarbon Carbonyl) cyclopropyl] carbonyl, ethoxy (oxo) acetyl, [(aminocarbonyl) amino] carbonyl, amino (oxo) acetyl, 2,3-dihydroxypropanoyl, (2S) -2,3 -Dihydroxypropanoyl and trifluoroacetyl

As used herein, the term "C _{1 -6-alkyl} acyl" refers to a C _{1 -6} alkyl having an acyl substituent as defined above herein.

As used herein, the term “3 to 8 membered heterocycloalkyl” refers to 3 to 8 as defined herein above in which one, two or three carbon atoms are substituted with one, two or three atoms selected from O, S or N. 8-membered heterocycloalkyl. Said heterocycloalkyl is defined herein aminocarbonyl, C _{1 -6} alkylamino-carbonyl, C _{3 -8} cycloalkyl, C _{1 -6} alkyl, hydroxy, alkoxy carbonyl, C _{1 -6-alkyl} alkoxycarbonyl, groups with halogen, amino, oxo and C _{1 -6} one or more selected from alkyl, typically of any suitable, but not limited to one, with one of these comprises a two or three can be optionally substituted.

Examples of 3-8 membered heterocycloalkyl according to the present invention include piperidinyl, 4,4-difluoropiperidinyl, morpholin-4-yl, pyrrolidinyl, 4-isopropyl-piperazin, 3- (Dimethylamino) pyrrolidinyl, azepanyl, (2S) -2-methylpyrrolidinyl, (2R) -2-methylpyrrolidinyl, 2-methylpyrrolidinyl, thiomorpholin-4-yl, 1, 2,3,6-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, 2,3,4,5-tetrahydro-1H-azinyl, 1-oxidothiomorpholine-4 -Yl or tetrahydro-2H-pyran-4-yl.

As used herein, the term "C _{1 -6-alkyl} heterocycloalkyl" refers to a C _{1 -6} alkyl substituted with a heterocycloalkyl, as defined herein above.

As used herein, the terms used in the "C _{2 -6} - alkenyl cycloalkyl" means a C _{2 -6} alkenyl optionally substituted with a cycloalkyl, as defined herein above.

As used herein, the term "C _{2 -6-alkenyl} heterocycloalkyl" is a C _{2 -6} substituted by a heterocycloalkyl as defined herein above; means an alkenyl.

As used herein, the term "C _{2 -6} - alkynyl cycloalkyl" means a C _{2 -6-alkynyl} substituted with a cycloalkyl, as defined herein above.

As used herein, the term "C _{2 -6-alkynyl} heterocycloalkyl" is a C _{2 -6} substituted by a heterocycloalkyl as defined herein above; means the alkynyl.

The term "aryl acyl" as used herein, means an aryl group having an acyl substituent as defined above herein.

As used herein, the term “heteroaryl acyl” refers to a heteroaryl group having an acyl substituent as defined above herein.

As used herein, the terms used in the "C _{3 -8} - (hetero) cycloalkyl acyl" means a 3 to 8 membered heterocycloalkyl having an acyl substituent as defined above herein.

The term "amino" as used herein refers to aliphatic groups of formula -NR ^c R ^d, wherein R ^c and R ^d are independently hydrogen, "C _{2 -6} alkenyl", "C _{1 -6-alkyl",} " C _{2 -6-alkynyl} "," C _{3 -8-cycloalkyl} "," heterocycloalkyl "," aryl "," heteroaryl "," C _{1 -6-alkyl} aryl "," C _{1 -6-alkyl} heteroaryl " , "C _{1 -6-alkyl} cycloalkyl" or "C _{1 -6} alkyl heterocycloalkyl group"or; A cyclic group of formula NR ^c R ^d , wherein R ^c and R ^d are joined together with nitrogen to form a 3-8 membered, preferably 5-7 membered heterocycloalkyl as defined herein.

Examples of "amino" groups according to the invention include amino, dimethylamino, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, morpholin-4-yl, thiomorpholine- 4-yl, pyrrolidin-1-yl, azepan-1-yl, 4- (isopropyl) piperazin-1-yl, 2-methylpyrrolidin-1-yl, (2S) -2-methyl Pyrrolidin-1-yl, (2R) -2-methylpyrrolidin-1-yl, (3R) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) pyrrolidine -1-yl and 4-cyclopentyl-piperazin-1-yl.

As used herein, the term "C _{1 -6-alkylamino"} represents a substituted C _1-6 alkyl amino groups defined above.

As used herein, the term “aminocarbonyl” refers to a group of the formula —C (O) NR ^c R ^d where R ^c and R ^d are as defined herein above for amino groups. "Aminocarbonyl" according to the present invention includes aminocarbonyl, morpholin-4-ylcarbonyl and (ethylamino) carbonyl.

As used herein, the term "C _{1 -6-alkyl} aminocarbonyl" refers to a C _{1 -6} alkyl substituted with an aminocarbonyl wherein as defined herein. Examples of the C _{1 -6} alkylamino-carbonyl according to the invention has a 2-amino-2-oxoethyl.

As used herein, the term "C _{3 -8} - cycloalkylamino" represents a substituted C _{3 -8} cycloalkyl amino groups defined above.

As used herein, the term “acylamino” refers to a group of the formula —NR ^c C (O) R ^d , wherein R ^c and R ^d are as defined above for the amino group.

As used herein, the term "C _{1 -6-alkyl} acylamino" refers to a C _{1 -6} alkyl substituted with an acylamino, as defined herein above.

As used herein, the term "carboxy" refers to a group of the formula -COOH.

As used herein, the term "C _{1 -6-alkyl} carboxy" refers to a C _{1 -6} alkyl substituted with carboxyl.

As used herein, the term "cyano" refers to a group of the formula -CN.

The term "alkoxy carbonyl" group is -C (O) indicate the OR ^g, wherein R ^g is a "C _{1 -6-alkyl",} "C _{2 -6} alkenyl", "C _{2 -6-alkynyl",} "C _3-8 cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C _{1 -6-alkyl} aryl "or" C _{1 -6-alkyl} heteroaryl "," C _{2 -6} - alkylcycloalkyl "," it includes a C _{1 -6-alkyl} heterocycloalkyl ". Examples of alkoxycarbonyl according to the invention are tert-butoxycarbonyl, methoxycarbonyl and ethoxycarbonyl.

The term "C _{1 -6-alkyl} alkoxycarbonyl" refers to C _{1 -6} alkyl having an alkoxycarbonyl as defined herein above as a substituent. An example of C 1-6 alkyl alkoxycarbonyl according to the invention is 2-methoxy-2-oxoethyl.

As used herein, the term “acyloxy” refers to a group of the formula —0C (= 0) R ^b , where R ^b is as defined herein above for the acyl group.

As used herein, the term "C _{1 -6-alkyl} acyloxy" refers to a C _{1 -6} alkyl substituted with an acyloxy group as defined herein above.

The term "acyl-aminocarbonyl" group is a ^{-C (0) NR h C (} 0) represent the R ^i, wherein R ^h and R ⁱ are independently hydrogen, "C _{1 -6-alkyl",} "C _{2 -6} al alkenyl "," C _{2 -6-alkynyl} "," C _{3 -8-cycloalkyl} "," heterocycloalkyl "," aryl "," heteroaryl "," C _{1 -6-alkyl} aryl "or" C _{1 -6} alkyl heteroaryl "," C _{2 -6} - represents an alkyl cycloalkyl "," C _{1 -6-alkyl} heterocycloalkyl ".

As used herein, the term "ureido" refers to a group of the formula -NR ⁱ C (O) NR ^c R ^d , where R ⁱ is R ^c Or as defined herein above for R ^d and R ^c And R ^d is as defined above for the amino group. R 'is typically H or C _{1 -4} alkyl.

As used herein, the term "C _{1 -6-alkyl} ureido" refers to C _{1 -6} alkyl substituted by a urea Ido above defined herein. Examples of the C _{1 -6} alkyl urea Ido has a [(aminocarbonyl) amino] methyl.

As used herein, the term “carbamate” refers to a group of the formula —NR ^c C (O) OR ^d , wherein R ^c and R ^d are as defined herein above for amino groups.

As used herein, the terms used in the "C _{1 -6} alkyl carbamate" refers to C _{1 -6} alkyl substituted by a carbamate as defined herein above.

The term "oxo" as used herein means = 0.

As used herein, the term "thioxo" means = S.

As used herein, the term "sulfonyl" is to mean a group of the formula ^"k -S0 ₂ -R", wherein R ^k is substituted with H, "aryl", "heteroaryl", "C _{1 -6} alkyl", halogen the "C _{1 -6} alkyl", for example, -SO2-CF ₃ group, "C _{2 -6} alkenyl", "C _{2 -6-alkynyl",} "C _{3 -8-cycloalkyl",} "heterocycloalkyl "," aryl "," heteroaryl "," C _{1 -6-alkyl} aryl "or" C _{1 -6-alkyl} heteroaryl "," C _{2 -6} - alkenyl aryl "," C _{2 -6} - alkenyl heteroaryl aryl "," C _{2 -6-alkynyl} is selected from heteroaryl "," C _{1 -6-alkyl} cycloalkyl "or" C _{1 -6-alkyl} heterocycloalkyl "alkynyl aryl", "C _{2 -6.}

As used herein, the term "C _{1 -6} alkyl sulfonyl" means a C _{1 -6} alkyl substituted with a sulfonyl above defined herein.

As used herein, the term "sulfonyloxy" refers to a group of the formula "-OSO ₂ -R ^k ", where R ^k is as defined herein above for the sulfonyl group.

As used herein, the term "C _{1 -6-alkyl} sulfonyloxy" refers to a C _{1 -6} alkyl substituted with a sulfonyloxy defined herein above.

As used herein, the term “aminosulfonyl” refers to a group of the formula —SO ₂ —NR ^c R ^d —, wherein R ^c and R ^d are as defined herein above for the amino group. An example of an aminosulfonyl group according to the present invention is morpholin-4-ylsulfonyl.

As used herein, the term "C _{1 -6-alkyl} aminosulfonyl" refers to a C _{1 -6} alkyl substituted with aminosulfonyl as defined herein above.

As used herein, the term "sulfinyl" means "-S (O) -R ^k ", where R ^k is as defined herein above for the sulfonyl group.

As used herein, the term "C _{1 -6} alkyl sulfinyl" refers to a C _{1 -6} alkyl substituted with a sulfinyl above defined herein.

As used herein, the term “sulfanyl” refers to a group of the formula —SR ^k , where R ^k is as defined above herein for the sulfonyl group.

As used herein, the term "C _{1 -6-alkyl} sulfanyl" refers to a C _{1 -6} alkyl substituted with a sulfanyl above defined herein.

As used herein, the term “sulfonylamino” refers to the group —NR ^c SO ₂ —R ^k , wherein R ^k is as defined herein above for the sulfonyl group and R ^c is as defined above herein for the amino group. same.

As used herein, the term "C _{1 -6-alkyl} sulfonylamino" refers to a C _{1 -6} alkyl substituted by a sulfonylamino defined herein above.

As used herein, the term "phosphonate" refers to a group of the formula -P (O)-(OR ^m ) ₂ , where R ^m is an alkyl group as defined above herein. The term "C _{1 -6} alkyl phosphonate" refers to groups substituted with C _{1 -6} alkyl, by a "phosphonate" the described herein. Examples of "C _{1 -6} alkyl phosphonate" in accordance with the present invention is methyl [bis (ethyloxy) phosphoryl].

The term "phosphono" as used herein refers to a group of the formula -P (O)-(OH) ₂ .

The term "C _{1 -6} alkyl phosphono" refers to groups substituted with C _{1 -6} alkyl, in a "phosphono," as described herein. Examples of "C _{1 -6} alkyl phosphono" according to the present invention there is phosphono methyl.

Unless otherwise included by the definition of an individual substituent, all groups defined above may be substituted or unsubstituted.

By the "optionally substituted" as used herein does not contain, unlike by the definition of the individual substituent, "C _{1 -6-alkyl",} "C _{2 -6} alkenyl", "C _{2 -6-alkynyl",} "aryl" and "heteroaryl" groups are optionally in the listed such as "C _{1 -6-alkyl",} "C _{2 -6} alkenyl", "C _2-6 alkynyl", "cycloalkyl", "heterocycloalkyl "," C _{1 -6-alkyl} aryl "," C _{1 -6-alkyl} heteroaryl "," C _{1 -6-alkyl} cycloalkyl "," C _{1 -6-alkyl} heterocycloalkyl "," C _{1 -6} alkyl, hydroxy "," Amino "," ammonium "," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," ureido "," carbamate "," aryl " , "Heteroaryl", "sulfinyl", "sulfonyl", "aminosulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy, Substitution with 1 to 5 substituents selected from the group consisting of nitro, phosphonate and the like Can be.

In one embodiment according to the present invention, A may represent a group of the formula -NR ⁴ R ^5, wherein R ⁴ and R ⁵ is a substituted or unsubstituted C _{1 -6} alkyl, optionally substituted C _{2 -6} independently alkenyl, optionally substituted C _{2 -6-alkynyl,} optionally substituted C _{3 -8} cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted C _{1 -6} alkyl, aryl, substituted or unsubstituted C _{1 -6-alkyl-heteroaryl,} optionally substituted C _{1 -6} alkyl, cycloalkyl, or an optionally substituted C _{1 -6} alkyl or a heterocycloalkyl group; A is a 3-8 membered substituted or unsubstituted heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom.

In another embodiment according to the present invention, A is a group -NR inde ⁴ R ^5, wherein R ⁴ and R ⁵ are independently an optionally substituted C _{1 -6} alkyl; A is a 3-8 membered substituted or unsubstituted heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom.

In one particular embodiment according to the invention, A is a 3-8 membered substituted or unsubstituted heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom.

In another specific embodiment according to the invention, A is optionally substituted piperidin-1-yl, optionally substituted morpholin-4-yl, optionally substituted pyrrolidin-1- A nitrogen atom selected from the group comprising or consisting of one, substituted or unsubstituted piperazin-1-yl, substituted or unsubstituted azepan-1-yl, or substituted or unsubstituted thiomorpholin-4-yl To 3-8 membered heterocycloalkyl linked to a cyclobutyl group via.

Representative examples of A according to the present invention include pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, (2S) -2-methylpyrrolidin-1-yl, (2R) -2-methyl Pyrrolidin-1-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, morpholin-4-yl, (3R) -3- (dimethylamino) pyrroli Din-1-yl, 3- (dimethylamino) pyrrolidin-1-yl, azepan-1-yl, thiomorpholin-4-yl, 4-isopropylpiperazin-1-yl and 4-cyclopentyl Piperazin-1-yl.

In one specific embodiment according to the invention, A is selected from substituted or unsubstituted piperidin-1-yl, and substituted or unsubstituted pyrrolidin-1-yl. Examples of A according to this particular embodiment are piperidin-1-yl, 2-methylpyrrolidin-1-yl, (2S) -2-methylpyrrolidin-1-yl or (2R) -2- Methylpyrrolidin-1-yl.

In another specific embodiment, A is piperidin-1-yl, (2S) -2-methylpyrrolidin-1-yl or (2R) -2-methylpyrrolidin-1-yl.

In a further particular embodiment, A is piperidin-1-yl.

In another specific embodiment, A is (2S) -2-methylpyrrolidin-1-yl.

In yet another specific embodiment, A is (2R) -2-methylpyrrolidin-1-yl.

A ¹ may be CH, CF or N.

In one embodiment, A ¹ is CH or CF.

In one particular embodiment according to the invention, A ¹ is CH.

In one embodiment according to the invention, B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl .

In another embodiment according to the invention, B is substituted or unsubstituted 5, 6 or 7 membered cyclo selected from the group comprising tetrahydropyridyl, tetrahydro-1H-azinyl, cyclopentenyl or pyridyl Alkyl, optionally substituted 5, 6 or 7 membered heterocycloalkyl, or optionally substituted heteroaryl.

In certain embodiments according to the invention, B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl, It is combined with an oxazole, thiazole or imidazole ring to form 4,5,6,7-tetrahydro [1,3] thiazolopyridine, 4,5,6,7-tetrahydro [1,3] oxazolopyridine. , 4,5,6,7-tetrahydro-1H-imidazopyridine, 5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole, 5,6,7,8-tetrahydro -4H- [1,3] thiazoloazepine, 5,6,7,8-tetrahydro-4H- [1,3] oxazoloazine, 1H-imidazopyridine and [1,3] thiazolopyridine To form a fused heterocycle selected from the group consisting of:

Examples of such heterocycles include 4,5,6,7-tetrahydro [1,3] thiazolo [5,4-pyridine, 4,5,6,7-tetrahydro [1,3] thiazolo [4 , 5-b] pyridine, 4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine, 4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine, 4,5,6,7-tetrahydro-3H-imidazo [4,5-c] pyridine, 5,6,7,8-tetrahydro-4H- [1,3 ] Thiazolo [5,4-b] azepine, 5,6,7,8-tetrahydro-4H- [1,3] oxazolo [5,4-b] azepine, 5,6-dihydro- 4H-cyclopenta [d] [1,3] thiazole, 3H-imidazo [4,5-c] pyridine and [1,3] thiazolo [4,5-c] pyridine.

In a further specific embodiment, B forms together with the thiazole ring a fused heterocycle comprising 4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine.

In one particular embodiment according to the invention X is O.

In another specific embodiment, X is S.

In one particular embodiment according to the invention Y is S.

In another particular embodiment, Y is O.

In one further embodiment, Y is NH.

In one embodiment according to the present invention, R ¹ is optionally substituted C _{1 -6} alkyl, substituted or non-aryl, unsubstituted or substituted unsubstituted heteroaryl, substituted or unsubstituted C- _3-8 cycloalkyl , substituted or non-3- to 8-membered heterocycloalkyl, acyl, optionally substituted non-substituted C _{1 -6} alkyl, cycloalkyl, optionally substituted C _{1 -6} alkyl, heterocycloalkyl, alkoxycarbonyl, aminocarbonyl , optionally substituted C _{1 -6} alkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkylamino-carbonyl, hydroxy, halogen, cyano, carboxy, oxo, the group which contains or consists of thioxo Is selected from; n is 0 or 1;

In another embodiment according to the present invention, R ² is optionally substituted C _{1 -6} include alkyl, hydroxy, oxo, or is selected from the group consisting therefrom; n is 0 or 1;

In one particular embodiment according to the invention n is zero.

In one embodiment according to the present invention, R ² is hydrogen, carboxy, sulfonyl, amino, optionally substituted C _{1 -6} alkyl, alkenyl optionally substituted C _{2 -6} alkenyl, optionally substituted C _2-6 alkynyl, substituted or non-aryl, heteroaryl, substituted or unsubstituted substituted or unsubstituted non-substituted C _{3 -8} cycloalkyl, an optionally substituted 3- to 8-membered heterocycloalkyl, acyl, substituted or unsubstituted C _{1 -6} alkyl, aryl, optionally substituted C _{1 -6-alkyl-heteroaryl,} substituted or unsubstituted C _{2 -6} - alkenyl aryl, substituted or unsubstituted C _{2 -6} - alkenyl heteroaryl aryl, optionally substituted C _{2 -6} - alkynyl aryl, substituted or unsubstituted C _{2 -6} - alkynyl heteroaryl, optionally substituted C _{1 -6} alkyl, cycloalkyl, optionally substituted C _1-6 eggs Heterocycloalkyl, substituted or unsubstituted C _{2 -6} - alkenyl, cycloalkyl, optionally substituted C _{2 -6} - non-alkenyl heterocycloalkyl, optionally substituted C _{2 -6} - alkynyl cycloalkyl, optionally substituted C _{2 -6} - alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6} alkyl carboxy, optionally substituted C _{1 -6} alkyl, acyl, substituted or are aryl acyl, heteroaryl acyl, optionally substituted optionally substituted non-substituted C _{3 -8} - (hetero) cycloalkyl acyl, optionally substituted C _{1 -6} alkyl acyloxy, substituted or unsubstituted C _1-6 alkyl, alkoxy, are optionally substituted with C _{1 -6-alkyl} alkoxycarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} optionally substituted C _{1, 5} -Alkyl acylamino, acylamino, ureido, substituted or unsubstituted C _{1 -6-alkyl} ureido, substituted or unsubstituted C _{1 -6-alkyl} carbamate, unsubstituted or substituted C _{1 -6} alkylamino, aminosulfonyl, optionally substituted C _{1 -6} alkyl aminosulfonyl, hydroxy, optionally substituted C _{1 -6} alkyl, hydroxy, phosphonate, substituted or unsubstituted C _{1 -6} alkyl phosphonium carbonate, is selected from the group comprising substituted or non-substituted C _{1 -6} alkyl, phosphono, oxo, and thioxo.

In another embodiment according to the present invention, R ² is hydrogen, carboxy, sulfonyl, unsubstituted or unsubstituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, optionally substituted C _{2 - 6-alkynyl,} substituted or non-aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-substituted C _{3 -8} cycloalkyl, an optionally substituted 3- to 8-membered heterocycloalkyl, acyl, optionally substituted are C _{1 -6} alkyl, cycloalkyl, optionally substituted C _{1 -6} alkyl, heterocycloalkyl, alkoxycarbonyl, are C _{1 -6-alkyl} alkoxycarbonyl, aminocarbonyl, optionally substituted optionally substituted C _1-6 alkyl aminocarbonyl, acylamino, ureido, an optionally substituted C _{1 -6} alkyl ureido, substituted or unsubstituted C _{1 -6} alkyl carbamate, amino, Chi Are unsubstituted or C _{1 -6} alkylamino, aminosulfonyl, hydroxy, are optionally substituted C _{1 -6} alkyl, hydroxy, optionally substituted C _{1 -6} alkyl phosphonate, substituted or unsubstituted C _{1 -6} alkyl is selected from the group consisting of phosphono and oxo.

In a further one embodiment of the present invention R ² is hydrogen, carboxy, acyl, optionally substituted C _{3 -8} cycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, alkoxycarbonyl, amino carbonyl, optionally substituted C _{1 -6} alkyl, aminocarbonyl, aminosulfonyl, optionally substituted C _{1 -6} alkyl, hydroxy, optionally substituted C _{1 -6} alkyl phosphonates and substituted or It includes compounds of formula (I) selected from the group consisting of unsubstituted C _{1 -6} alkyl phosphono.

Examples of R ² according to this further embodiment are hydrogen, carboxy, methoxyacetyl, tert-butoxycarbonyl, acetyl, morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, aminoacetyl, amino Carbonyl, hydroxyacetyl, 2,3-dihydroxypropyl, (2S) -2,3-dihydroxypropyl, (2R) -2,3-dihydroxypropyl, 2-amino-2-oxoethyl , (Ethylamino) carbonyl, 3-hydroxycyclobutyl, 3-amino-3-oxopropanoyl, 2-methoxy-2-oxoethyl, [bis (ethyloxy) phosphoryl] methyl, 3,3 , 3-trifluoropropanoyl, phosphonomethyl, (5-methyl-2H-1,2,3-triazol-4-yl) carbonyl, 2-hydroxyethyl, 4- (1-oxy degree Thiomorpholin-4-yl) butanoyl, 3- (acetylamino) propanoyl, (carboxymethoxy) acetyl, 3,3,3-trifluoro-2-hydroxypropanoyl, tetrahydro-2H -Pyran-4-ylcarbonyl, (1-hydroxycyclopropyl) carbonyl, [(1-aminocarbonyl) Clopropyl] carbonyl, ethoxy (oxo) acetyl, [(aminocarbonyl) amino] carbonyl, amino (oxo) acetyl, 2,3-dihydroxypropanoyl, 2-hydroxy-3,4- Dioxocyclobut-1-en-1-yl, 3,4-dioxo-2- (propan-2-yloxy) cyclobut-1-en-1-yl, 2-amino-3,4-di Oxocyclobut-1-en-1-yl, (2S) -2,3-dihydroxypropanoyl and trifluoroacetyl.

In one specific embodiment, R ² is acetyl, aminoacetyl, aminocarbonyl, hydroxyacetyl, 2,3-dihydroxypropyl, (2S) -2,3-dihydroxypropyl, (2R) -2 , 3-dihydroxypropyl, 2-amino-2-oxoethyl, 3-hydroxycyclobutyl, 3-amino-3-oxopropanoyl, (5-methyl-2H-1,2,3-triazole -4-yl) carbonyl, 2-hydroxyethyl, (carboxymethoxy) acetyl, tetrahydro-2H-pyran-4-ylcarbonyl, [(1-aminocarbonyl) cyclopropyl] carbonyl, amino ( Oxo) acetyl, 2,3-dihydroxypropanoyl and 2-amino-3,4-dioxocyclobut-1-en-1-yl.

In another specific embodiment, R ² is selected from the group comprising or consisting of acetyl, aminocarbonyl, hydroxyacetyl, 2-amino-2-oxoethyl and amino (oxo) acetyl.

In one particular embodiment according to the invention m is 1.

In one embodiment according to the invention, R ³ is hydrogen or halogen.

In another embodiment according to the invention, R ³ is hydrogen or fluorine.

In one particular embodiment according to the invention, R ³ is hydrogen.

In one embodiment, the invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is a group of the formula -NR ⁴ R ^5, wherein R ⁴ and R ⁵ are independently substituted or unsubstituted C _{1 -6} alkyl, alkenyl optionally substituted C _{2 -6} alkenyl, optionally substituted C _2-6 alkynyl, substituted or unsubstituted C _{3 -8} cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted C _{1 -6} alkyl, aryl, optionally substituted C _{1 -6} alkyl heterocyclic aryl, optionally substituted C _{1 -6} alkyl, cycloalkyl or optionally substituted C _{1 -6} alkyl or a heterocycloalkyl group; A is a 3-8 membered substituted or unsubstituted heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom;

A ¹ is CH, C-halogen or N;

B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;

X is O or S;

Y is O, S or NH;

n is 0;

R ² is hydrogen, carboxy, sulfonyl, amino, optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, substituted or unsubstituted C _{2 -6-alkynyl,} optionally substituted that is an aryl, optionally substituted heteroaryl being substituted or unsubstituted C _{3 -8} cycloalkyl, an optionally substituted 3- to 8-membered heterocycloalkyl, acyl, optionally substituted C _{1 -6} alkyl, aryl , optionally substituted C _1-6 alkyl-heteroaryl, substituted or unsubstituted C _{2 -6} alkenyl aryl, optionally substituted C _{2 -6} - non-alkenyl heteroaryl, optionally substituted C _{2 - 6-alkynyl} aryl, substituted or unsubstituted C _{2 -6-alkynyl} heteroaryl, optionally substituted C _{1 -6} alkyl, cycloalkyl, optionally substituted C _{1 -6} alkyl heterocycloalkyl, substituted or It is not unsubstituted C _{2 -6} - alkenyl, cycloalkyl, optionally substituted C _{2 -6} - non-alkenyl heterocycloalkyl, optionally substituted C _{2 -6-alkynyl} cycloalkyl, substituted or unsubstituted C _{2 -6} alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6} alkyl carboxy, optionally substituted C _{1 -6} alkyl, acyl, aryl acyl which is unsubstituted or substituted, substituted or that is unsubstituted heteroaryl acyl, substituted or unsubstituted C _{3 -8} - (hetero) cycloalkyl acyl, optionally substituted C _{1 -6} alkyl, acyloxy, optionally substituted C _{1 -6} alkyl, alkoxy, substituted or unsubstituted C _{1 -6} alkyl, alkoxycarbonyl, substituted or not are C _{1 -6-alkyl-aminocarbonyl,} being optionally substituted optionally substituted C _{1 -6} alkyl, acyl, acylamino, Wu Ido, that is optionally substituted with C _{1 -6-alkyl} ureido, substituted or unsubstituted C _{1 -6-alkyl} carbamate, unsubstituted or substituted C _{1 -6} alkylamino, aminosulfonyl, optionally substituted C _{1 -6-alkyl} aminosulfonyl, hydroxy, are optionally substituted with C _1-6 alkyl, hydroxy, phosphonate, optionally substituted C _{1 -6} alkyl phosphonate, substituted or unsubstituted C _{1 -6} alkyl phosphono, oxo and thioxo;

m is 0 or 1;

R ³ is hydrogen or halogen.

In another embodiment, the invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is a group of the formula -NR ⁴ R ^5, wherein R ⁴ and R ⁵ are independently an optionally substituted C _{1 -6} alkyl; A is a 3-8 membered substituted or unsubstituted heterocycloalkyl linked through a nitrogen atom with a cyclobutyl group;

A ¹ is CH or CF;

B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;

X is O or S;

Y is O, S or NH;

n is 0;

R ² is hydrogen, carboxy, sulfonyl, optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, substituted or unsubstituted C _{2 -6-alkynyl,} substituted or unsubstituted aryl, optionally substituted heteroaryl, an optionally substituted C _{3 -8} cycloalkyl, that are optionally substituted 3 to 8 membered heterocycloalkyl, unsubstituted acyl, optionally substituted C _{1 -6} alkyl, cycloalkyl, optionally substituted C _{1 -6} alkyl, heterocycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6} alkylamino-carbonyl, acylamino, ureido, substituted or unsubstituted C _{1 -6-alkyl} ureido, substituted or unsubstituted C _{1 -6} alkyl carbamate, amino, optionally substituted C _{1 -6} al Amino, aminosulfonyl, hydroxy, optionally substituted C _{1 -6} alkyl, hydroxy, optionally substituted C _{1 -6} alkyl phosphonate, optionally substituted C _{1 -6} alkyl phosphono and oxo Selected from the group consisting of;

m is 0 or 1;

R ³ is hydrogen or fluorine.

In a further embodiment, the invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is a 3-8 membered substituted or unsubstituted heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom;

A ¹ is CH;

B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted, selected from the group comprising or consisting of tetrahydropyridyl, tetrahydro-1H-azinyl, cyclopentenyl and pyridyl Unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;

X is O or S;

Y is O, S or NH;

n is 0;

R ² is hydrogen, carboxy, acyl, optionally substituted C _{3 -8} cycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, non-alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} aminosulfonyl, optionally substituted C _{1 -6} alkyl, hydroxy, non-substituted or unsubstituted C _{1 -6} alkyl phosphonate and optionally substituted C _{1 -6} alkyl phosphonoacetate It is selected from the group consisting or consisting of;

m is 0 or 1;

R ³ is hydrogen.

 In one particular embodiment, the present invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is substituted or unsubstituted piperidin-1-yl, substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted pyrrolidin-1-yl, substituted or unsubstituted piperazine-1- One, a 3-8 membered heterocycloalkyl linked to cyclobutyl via a nitrogen atom selected from the group consisting of substituted or unsubstituted azepanyl or substituted or unsubstituted thiomorpholin-4-yl;

A ¹ is CH;

B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl, which is an oxazole, thiazole or imidazole 4,5,6,7-tetrahydro [1,3] thiazolopyridine, 4,5,6,7-tetrahydro [1,3] oxazolopyridine, 4,5,6,7-tetra with ring Hydro-1H-imidazopyridine, 5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole, 5,6,7,8-tetrahydro-4H- [1,3] thiazolo To form a fused heterocycle comprising azepine, 5,6,7,8-tetrahydro-4H- [1,3] oxazoloazine, 1H-imidazopyridine and [1,3] thiazolopyridine ;

X is O or S;

Y is O, S or NH;

n is 0;

R ² is hydrogen, carboxy, acyl, optionally substituted C _{3 -8} cycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, non-alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} aminosulfonyl, optionally substituted C _{1 -6} alkyl, hydroxy, it is optionally substituted C _{1 -6} alkyl phosphonate and phosphonate, optionally substituted C _{1 - 6} alkyl phosphono selected from the group consisting of or consisting of;

m is 0 or 1;

R ³ is hydrogen.

In one particular embodiment, the present invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, (2S) -2-methylpyrrolidin-1-yl, (2R) -2-methylpyrrolidin-1-yl , Piperidin-1-yl, 4,4-difluoropiperidin-1-yl, morpholin-4-yl, (3R) -3- (dimethylamino) pyrrolidin-1-yl, 3 -(Dimethylamino) pyrrolidin-1-yl, azepan-1-yl, thiomorpholin-4-yl, 4-isopropylpiperazin-1-yl and 4-cyclopentylpiperazin-1-yl 3 to 8 membered heterocycloalkyl selected from the group comprising;

A ¹ is CH;

B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl, which is an oxazole, thiazole or imidazole Together with the ring, 4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine, 4,5,6,7-tetrahydro [1,3] thiazolo [4, 5-b] pyridine, 4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine, 4,5,6,7-tetrahydro [1,3] oxazolo [ 4,5-c] pyridine, 4,5,6,7-tetrahydro-3H-imidazo [4,5-c] pyridine, 5,6,7,8-tetrahydro-4H- [1,3] Thiazolo [5,4-b] azepine, 5,6,7,8-tetrahydro-4H- [1,3] oxazolo [5,4-b] azepine, 5,6-dihydro-4H Fusion selected from the group consisting of -cyclopenta [d] [1,3] thiazole, 3H-imidazo [4,5-c] pyridine, and [1,3] thiazolo [4,5-c] pyridine Form a heterocycle;

X is O or S;

Y is O, S or NH;

n is 0;

R ² is hydrogen, carboxy, methoxyacetyl, tert-butoxycarbonyl, acetyl, morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, aminoacetyl, aminocarbonyl, hydroxyacetyl, 2 , 3-dihydroxypropyl, (2S) -2,3-dihydroxypropyl, (2R) -2,3-dihydroxypropyl, 2-amino-2-oxoethyl, (ethylamino) carbonyl, 3-hydroxycyclobutyl, 3-amino-3-oxopropanoyl, 2-methoxy-2-oxoethyl, [bis (ethyloxy) phosphoryl] methyl, 3,3,3-trifluoropropano Yl, phosphonomethyl, (5-methyl-2H-1,2,3-triazol-4-yl) carbonyl, 2-hydroxyethyl, 4- (1-oxidodothiomorpholin-4-yl) Butanoyl, 3- (acetylamino) propanoyl, (carboxymethoxy) acetyl, 3,3,3-trifluoro-2-hydroxypropanoyl, tetrahydro-2H-pyran-4-ylcarbonyl , (1-hydroxycyclopropyl) carbonyl, [(1-aminocarbonyl) cyclopropyl] carbonyl, ethoxy (jade ) Acetyl, [(aminocarbonyl) amino] carbonyl, amino (oxo) acetyl, 2,3-dihydroxypropanoyl, 2-hydroxy-3,4-dioxocyclobut-1-ene-1 -Yl, 3,4-dioxo-2- (propan-2-yloxy) cyclobut-1-en-1-yl, 2-amino-3,4-dioxocyclobut-1-ene-1- One, (2S) -2,3-dihydroxypropanoyl and trifluoroacetyl;

m is 0 or 1;

R ³ is hydrogen

In another specific embodiment, the invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is piperidin-1-yl, 2-methylpyrrolidin-1-yl, (2S) -2-methylpyrrolidin-1-yl or (2R) -2-methylpyrrolidin-1-yl ego;

A ¹ is CH;

B together with thiazole forms 4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

X is O;

Y is S;

n is 0;

R ² is acetyl, aminoacetyl, aminocarbonyl, hydroxyacetyl, 2,3-dihydroxypropyl, (2S) -2,3-dihydroxypropyl, (2R) -2,3-dihydroxypropyl , 2-amino-2-oxoethyl, 3-hydroxycyclobutyl, 3-amino-3-oxopropanoyl, (5-methyl-2H-1,2,3-triazol-4-yl) carbonyl , 2-hydroxyethyl, (carboxymethoxy) acetyl, tetrahydro-2H-pyran-4-ylcarbonyl, [(1-aminocarbonyl) cyclopropyl] carbonyl, amino (oxo) acetyl, 2,3 -Dihydroxypropanoyl and 2-amino-3,4-dioxocyclobut-1-en-1-yl;

m is 1;

R ³ is hydrogen.

In a further specific embodiment, the invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where

A is piperidin-1-yl, (2S) -2-methylpyrrolidin-1-yl or (2R) -2-methylpyrrolidin-1-yl;

A ¹ is CH;

B together with thiazole forms 4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

X is O;

Y is S;

n is 0;

R ² is selected from the group consisting of acetyl, aminocarbonyl, hydroxyacetyl, 2-amino-2-oxoethyl and amino (oxo) acetyl;

m is 1;

R ³ is hydrogen.

In one aspect, the invention relates to compounds of formula (Ia), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein A, A ¹ , X, Y, R ¹ , R ² , R ³ and n are as defined herein above and B is heteroaryl or 5-8 membered heterocycloalkyl.

The embodiments described herein above for A, A ¹ , X, Y, B, R ¹ , R ² , R ³ and n in compounds of formula (I) are also A, A in compounds of formula (Ia) ^The same applies to ¹ , X, Y, B, R ¹ , R ² , R ³ and n.

In another aspect, the present invention relates to compounds of formula (Ib), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein A, A ¹ , X, Y, R ¹ , R ² , R ³ and n are as defined herein above and B is a 5-8 membered cycloalkyl.

The embodiments described herein above for A, A ¹ , X, Y, B, R ¹ , R ² , R ³ and n in compounds of formula (I) are also A, A in compounds of formula (Ib) ^The same applies to ¹ , X, Y, B, R ¹ , R ² , R ³ and n.

In one aspect, the present invention relates to compounds of formula (Ic), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein A, A ¹ , X, Y, R ² and R ³ are as defined above.

Embodiments described herein above for A, A ¹ , X, Y, R ² and R ³ in compounds of formula (I) are also A, A ¹ , X, Y, R in compounds of formula (Ic) ^The same applies to ² and R ³ .

In another aspect, the invention relates to compounds of formula (Id), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein A ¹ , X, Y, B, R ² , R ³ And m is as defined herein.

Formula (I) A ^1, X, Y in the compound of, B, R ² and R ³ Further examples of the specific above-described herein for in the compound of formula ^{(Id) A 1, X,} Y, B, R ^The same applies to ² and R ³ .

In another embodiment, the invention relates to compounds of formula (Ie), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein X, Y, R ² and R ³ are as defined herein.

The embodiments described herein above for X, Y, R ² and R ³ in compounds of formula (I) also apply to X, Y, R ² and R ³ in compounds of formula (Ie).

 In another aspect, the present invention relates to compounds of formula (If), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein A, A ¹ , B, Y, R ² , R ³ , m and n are as defined herein.

The embodiments described herein above for A, A ¹ , Y, B, R ² , R ³ , m and n in compounds of formula (I) are also A, A ¹ , X in compounds of formula (If) The same applies to, Y, B, R ² , R ³ , m and n.

In one particular embodiment, the present invention

A is a 3-8 membered heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom;

A ¹ is CH;

Y is O, S or NH;

B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl selected from the group comprising or consisting of tetrahydropyridyl, tetrahydro-1H-azinyl, cyclopentenyl or pyridyl, substituted or unsubstituted Unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;

R ² is hydrogen, carboxy, acyl, optionally substituted C _{3 -8} cycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, non-alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} aminosulfonyl, optionally substituted C _{1 -6} alkyl, hydroxy, optionally substituted C _{1 -6} alkyl phosphonate, and optionally substituted C _{1 -6} alkyl phosphonium Is selected from the group consisting of phono;

m is 1;

A compound of formula (If) wherein R ³ is hydrogen or halogen.

In one particular aspect, the invention relates to compounds of formula (I), geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Wherein A, R ¹ and R ² are as defined herein.

According to one particular embodiment of the compounds of formulas (la), (lb) and (lc), the A and X groups attached to the A-cyclobutyl-X moiety are in trans configuration.

According to one particular embodiment of the compounds of the formulas (Id) and (Ie), X is attached to a cyclobutyl group at a piperidin-1-yl, and (piperidin-1-yl) -cyclobutyl-X residue The group is in trans coordination.

According to one particular embodiment of compounds of Formulas (If) and (Ig), the A and O groups attached to cyclobutyl at the A-cyclobutyl-0 residue are in trans configuration.

For R ² and R ³ in the compounds of formula (I) the above embodiments also apply to R ² and R ³ in the compounds of formula (If).

Examples of compounds according to the invention include the following:

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5- Carboxylic acid;

5- (methoxyacetyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thia Zolo [5,4-c] pyridine;

Tert-butyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridine-5 (4H) -carboxylate;

5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] Pyridine;

5- (morpholin-4-ylcarbonyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [ 1,3] thiazolo [5,4-c] pyridine;

5- (morpholin-4-ylsulfonyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1 , 3] thiazolo [5,4-c] pyridine;

5-acetyl-2- {4-[(trans-3-morpholin-4-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4 -c] pyridine;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] ethanamine;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 ( 4H) -carboxamide;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] ethanol;

5-acetyl-2- (4-{[trans-3- (4-isopropylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine;

5-acetyl-2- (4-{[trans-3- (4,4-difluoropiperidin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [ 1,3] thiazolo [5,4-c] pyridine;

5-acetyl-2- {4-[(trans-3-pyrrolidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;

3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] propane-1,2-diol;

(2S) -3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propane-1,2-diol;

(2R) -3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propane-1,2-diol;

2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] acetamide;

5-acetyl-2- {4-[(trans-3-azane-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4 -c] pyridine;

(3R) -1- {trans-3- [4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy Cy] cyclobutyl} -N, N-dimethylpyrrolidin-3-amine;

N-ethyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridine-5 (4H) -carboxamide;

5-acetyl-2- {4-[(trans-3-thiomorpholin-4-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;

5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) thio] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;

Cis-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c ] Pyridin-5 (4H) -yl] cyclobutanol;

3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propanamide;

Methyl [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine- 5 (4H) -yl] acetate;

Diethyl {[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] methyl} phosphonate;

5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] oxazolo [4, 5-c] pyridine;

5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4, 5-c] pyridine;

4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4, 5-b] pyridine;

4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} [1,3] thiazolo [4,5-c] pyridine;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5- (3,3,3-trifluoropropanoyl) -4,5,6,7 Tetrahydro [1,3] thiazolo [5,4-c] pyridine;

{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine- 5 (4H) -yl] methyl} phosphonic acid;

5-[(5-methyl-2H-1,2,3-triazol-4-yl) carbonyl] -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] Phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

5-acetyl-2- {2-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4.5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] ethanol;

5-acetyl-2- {2,6-difluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4,5,6,7-tetrahydro [1 , 3] thiazolo [5,4-c] pyridine;

5-acetyl-2- {3-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4.5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

5-acetyl-2- {2,3-difluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4,5,6,7-tetrahydro [1 , 3] thiazolo [5,4-c] pyridine;

5- [4- (1-oxydothiomorpholin-4-yl) butanoyl] -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4, 5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

N- {3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [ 5,4-c] pyridin-5 (4H) -yl] propyl} acetamide;

{2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, 4-c] pyridin-5 (4H) -yl] ethoxy} acetic acid;

1,1,1-trifluoro-3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [ 1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propan-2-ol;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5- (tetrahydro-2H-pyran-4-ylcarbonyl) -4,5,6,7 Tetrahydro [1,3] thiazolo [5,4-c] pyridine;

1-{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] carbonyl} cyclopropanol;

1-{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] carbonyl} cyclopropanecarboxamide;

1-{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] carbonyl} cyclopropanecarboxamide trifluoroacetate;

Ethyl oxo [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] acetate;

1- {trans-3- [4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy] cyclobutyl } -N, N-dimethylpyrrolidin-3-amine;

5-acetyl-2- (4-{[trans-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine;

1- {2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [ 5,4-c] pyridin-5 (4H) -yl] ethyl} urea;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] acetamide;

3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propane-1,2-diol;

3-hydroxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, 4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione;

3-isopropoxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5 , 4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione;

5-acetyl-2- [4-({trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine, isomer A;

3-amino-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione. 1/2 trifluoroacetate;

5-acetyl-2- [4-({trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine, isomer B;

(2S) -3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propane-1,2-diol;

5-acetyl-2- {4-[(cis-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro-3H-imidazo [4,5- c] pyridine;

5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro-3H-imidazo [4,5- c] pyridine;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5 -c] pyridin-5 (4H) -yl] ethanol;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5-c] pyridine-5 ( 4H) -carboxamide;

3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5 -c] pyridin-5 (4H) -yl] propanamide;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5 -b] pyridin-4 (5H) -yl] ethanol;

4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6,7,8-tetrahydro-4H- [1,3] oxazolo [5,4-b] azepine;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4- (trifluoroacetyl) -5,6,7,8-tetrahydro-4H- [1 , 3] oxazolo [5,4-b] azepine; And

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -3H-imidazo [4,5-c] pyridine.

In one particular embodiment, the invention relates to compounds of formula (I) selected from the group consisting of:

5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 ( 4H) -carboxamide;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] ethanol;

2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] acetamide;

2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] acetamide;

5-acetyl-2- [4-({trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine and enantiomers; And

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5-c] pyridine-5 ( 4H) -carboxamide.

Compounds of the invention are histidine H ₃ receptor ligands. In one embodiment, these compounds are histamine H ₃ receptor antagonists; In other embodiments these compounds are histamine H ₃ receptor inverse agonists.

In one embodiment, the compounds of the present invention have particularly advantageous drug properties, ie these compounds have low affinity for other receptors or proteins and good affinity for H ₃ receptors; They have desirable pharmacokinetics and pharmacodynamics with little or no side effects such as myocardial toxicity. One of the many methods known to measure the cardiovascular risk of drug compounds is to assess whether the test compound binds to hERG channels.

Compounds of the present invention show particularly low affinity for hERG channels.

In addition, preferred compounds according to the invention exhibit good brain H ₃ receptor occupancy.

"Pharmaceutically acceptable salts" according to the present invention include therapeutically active, nontoxic acid salts from which a compound of formula (I) may be formed.

The acid addition salt forms of the compounds of formula (I), which occur in free form as bases, can be used as the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Or organic acids such as acetic acid, trifluoroacetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, It can be obtained by treatment with a suitable acid, such as p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, palmoic acid and the like.

Conversely, the salt form can be converted to the free form by treatment with a suitable base.

Compounds of formula (I) and salts thereof may be in the form of solvates, which are included within the scope of the invention. Such solvates include, for example, hydrates, alcoholates and the like.

Some of the compounds of formula (I) and some of their intermediates have one or more stereocenters in their structure. Such solid centers may exist in the R or S configuration, wherein the R and S symbols are used according to the rules described in Pure Appl. Chem. 1976, 45, 11-30.

The invention also relates to all stereoisomeric forms of the compounds of formula (I), such as enantiomeric and diastereomeric forms, or mixtures thereof (including all possible mixtures of stereoisomers).

In the context of the present invention, the reference to a compound or compounds is intended to include the compounds in their respective possible isomeric forms and mixtures thereof, unless a specific isomeric form is specifically mentioned.

As used herein, the expression “enantiomerically pure” means a compound having greater than 95% enantiomeric excess (ee).

The compounds according to the invention may exist in different polymorphic forms. Such forms are included within the scope of the present invention, even if not expressly indicated by the above formula.

Compounds of formula (I), and prodrug forms of various subranges and subgroups thereof, are included within the scope of this application.

As used herein, the term “prodrug” includes a compound form which is rapidly converted into the parent compound according to the invention in vivo, for example by hydrolysis in blood. Prodrugs are compounds that include groups that are removed by biotransformation before exhibiting their pharmacological action. Such groups include residues that are readily cleaved in vivo from compounds comprising them, which compounds remain pharmacologically active or become pharmacologically active after cleavage. Groups cleavable by metabolism form a group well known to those skilled in the art. These include alkanoyls (ie, acetyl, propionyl, butyryl, etc.), substituted or unsubstituted carbocyclic aroyl (such as benzoyl, substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyls (e.g. Groups such as oxycarbonyl), trialkylsilyl (such as trimethyl- and triethylsilyl), monoesters (such as succinyl) formed using dicarboxylic acids, phosphates, sulfates, sulfonates, sulfonyl, sulfinyl and the like But not limited to these. Compounds containing groups cleavable by metabolism have the advantage that they may exhibit improved bioavailability as a result of improved solubility and / or absorption rates provided to the parent compound by the presence of groups cleavable by metabolism. Higuchi and V. Stella, "Pro-drugs as Novel Delivery System", Vol. 14 of the A.C.S. Symposium Series; "Bioreversible Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987].

Compounds of formula (I) according to the invention can be prepared according to conventional methods known to those skilled in the art of synthetic organic chemistry.

A. Compounds of formula (I) in which A ¹ is CH, X is oxygen and A, Y, B, R ¹ , R ² , R ³ , m and n have the same definition as described in the above formula Can be prepared by reacting a compound of formula (II) with a compound of formula (III):

In the above scheme, A ¹ is CH, P is hydrogen, and A, B, R ¹ , R ² , R ³ , Y, m and n have the same definitions as in the above formulas for compounds of formula (I) Have

This reaction is carried out in the presence of a base in a solvent, for example N, N-dimethylacetamide, for example sodium hydride, at a temperature in the range of 50 to 80 ° C. under an inert atmosphere, or any other that is considered suitable to those skilled in the art. Under conditions and according to conventional methods known to those skilled in the art.

In one particular embodiment, this method can also be used for the synthesis of compounds of formula (Ia) as defined above.

In another particular embodiment, this method can also be used for the synthesis of compounds of formula (Ib) as defined above.

Compounds of formula (III) may be prepared by reacting compounds of formula (IV) with p-toluenesulfonyl chloride or p-bromophenylsulfonyl chloride according to the following scheme:

In the above scheme, A has the same definition as above for the compound of formula (I), and X 'is methyl or bromide.

This reaction can be carried out using a base such as triethylamine or N-methylimidazole in a solvent such as dichloromethane at a temperature in the range of 0 ° C. to 25 ° C. under an inert atmosphere (argon or nitrogen), or known to those skilled in the art. It may be carried out according to any conventional method.

Compounds of formula (IV) may be prepared from compounds of formula (V) according to the following scheme:

In the above scheme, A has the same definition as described above for the compound of formula (I).

This reaction is carried out using a reducing agent such as sodium borohydride in a protic solvent such as ethanol at a temperature in the range of 0 ° C. to 60 ° C. under an inert atmosphere (argon or nitrogen), or in any conventional method known to those skilled in the art. Can be carried out accordingly.

Compounds of formula (V) may be obtained commercially or may be prepared from cyclobutane-1,3-dione by reaction with amines of formula AH according to the following scheme:

In the above scheme, A has the same definition as described above for the compound of formula (I).

This reaction may be carried out in a solvent such as dioxane at a temperature in the range of 0 ° C. to 30 ° C. under an inert atmosphere (argon or nitrogen) or may be carried out according to any conventional method known to those skilled in the art. Cyclobutane-1,3-dione is commercially available or may be prepared according to any conventional method known to those skilled in the art.

Compounds of formula (II) may be prepared according to one of the following methods:

A.1. Some compounds of formula (II), wherein Y is a sulfur atom and P is hydrogen or a protecting group, can be prepared by reacting a compound of formula (VII) with a compound of formula (VIII) according to the following scheme:

Wherein P is hydrogen or a protecting group, Y is sulfur and A ¹ , B, R ¹ , R ² , R ³ , m and n have the same definition as in the above formula for the compound of formula (I), Hal is a leaving group, preferably a bromine atom.

Examples of protecting groups may be benzyl groups, trialkylsilyl groups, tert-butoxy groups, acetyl groups, alkyl groups, or any other phenol-related protecting group deemed appropriate to those skilled in the art. Such protecting groups can be removed using any methodology and experimental conditions deemed appropriate to those skilled in the art and according to conventional methods known to those skilled in the art.

This reaction can be carried out in the presence of a solvent such as ethanol or iso-propanol at temperatures in the range of 50 ° C. to 100 ° C., or by Ashton, WT et al. In Bioorg. Med. Chem. Lett. 2005, 15, 2253 Or according to any other conventional method known to those skilled in the art.

In one particular embodiment, this method can be used for the synthesis of a compound of formula (II), hereinafter referred to as compound (IIa), in which P is hydrogen or a protecting group, and Y is S, B is a 5-8 membered heterocycloalkyl group containing a nitrogen atom, m is 1, R ² is linked to this nitrogen atom, R ² is connected to a nitrogen atom, A ¹ , R ¹ , R ² , R ³ and n have the same definitions as described above for the compound of formula (II).

In another specific embodiment, the same method can be used for the synthesis of the compound of formula (II), hereinafter referred to as compound (IIb), wherein in the compound of formula (IIb) P is hydrogen or a protecting group, Y is S, B is a 5-8 membered heterocycloalkyl group containing a nitrogen atom, m is 1, R ¹ One is an oxo group forming a lactam moiety, and A ¹ , R ¹ , R ² , n and R ³ have the same definitions as described above for the compound of formula (II). Preferably n is 1.

In another specific embodiment, the same method can be used for the synthesis of the compound of formula (II), hereinafter referred to as compound (IIc), in which P is hydrogen or a protecting group, and Y is S, B is a 5-8 membered cycloalkyl group, m is 1, R ² is alkoxycarbonyl, and A ¹ , R ¹ , R ³ , and n are as described above for the compound of formula (II) Have the same definition. Preferably n is zero.

Compounds of formula (VII) may be obtained commercially or may be prepared according to any conventional method known to those skilled in the art.

Compounds of formula (VIII), wherein Hal is a halogen atom and R ¹ , R ² , m and n are defined herein for compounds of formula (I), form compounds of formula (IX) according to the following scheme It can be prepared by reacting with:

This reaction is described in Marinko, P. et al. Eur. J. Med. Chem., 2004, 39, 257 or Habermann, J. et al. J. Chem. Soc, Perkin Trans. 1, 1999, 2425. Using bromine (Br ₂ ) or polymer supported pyridinium tribromide in a solvent such as dichloromethane or chloroform at temperatures in the range of 0 ° C. to 25 ° C. according to the described methods, or any conventional method known to those skilled in the art It can be carried out according to. Preferably, Hal is a bromine atom.

Alternatively, some compounds of formula (VIII) may be prepared in two steps according to the following schemes:

In the above scheme, W is a halogen atom, preferably a bromine atom, T is hydroxy, B is a 5-8 membered heterocycloalkyl or a 5-8 membered cycloalkyl, R ¹ , R ² , m and n Has the same definition as above.

Compounds of formula (VIII) may be prepared by the reaction of a "halohydrin" of formula (X) with an oxidizing agent such as Dess-Martin periodinan reagent or pyridinium chlorochromate, or known to those skilled in the art It may be prepared according to any conventional method.

Compounds of formula (X) can be obtained commercially. They also present the 5-8 membered cycloalkenes of formula (Xl) or 5-8 membered heterocycloalkenes according to the method described in Kim, W.-J. et al. In Heterocycles, 1995, 41, 1389. By reaction with a halogen releasing agent such as N-bromosuccinimide, or by any other method known to those skilled in the art.

Compounds of formula (Xl) may be obtained commercially or may be prepared according to any other conventional method known to those skilled in the art, for example compound (Xl) may be obtained from Yao, Q. et al. In Angew. Chem. Int. Ed., 2000, 39, 3896) can be prepared by intramolecular metathesis of di-alkenes.

A.2. Some compounds of formula (II) wherein P is hydrogen and A ¹ , B, R ¹ , R ² , R ³ , m and n have the same definitions as in the formulas described above for compounds of formula (I), Can be prepared by deprotecting the corresponding compound of formula (II), wherein is a protecting group. For example, when P is methyl or benzyl, this reaction can be carried out at room temperature using boron tribromide in a solvent such as dichloromethane, or using any other reagents and reaction conditions known to those skilled in the art. .

In one particular embodiment, compounds of formula (IIa) in which P is hydrogen can be obtained by deprotecting the corresponding compounds of formula (IIa) in which P is a protecting group.

A.3. Some compounds of formula (IIa) can be obtained by reducing the corresponding compounds of formula (IIb) according to the following scheme:

In the above scheme, P, A ¹ , R ¹ , R ² , R ³ and n have the same definitions as described above for the compound of formula (IIa). For example, this reaction may be carried out using a reducing agent such as a borane derivative (eg borane-dimethyl sulfide complex) in a solvent such as THF or ether and at a temperature in the range of 0 ° C. to 100 ° C., preferably at room temperature. Can be. Alternatively, this reaction can be carried out using other experimental conditions deemed appropriate to those skilled in the art and according to conventional methods known to those skilled in the art.

A.4. Some compounds of formula (IIa) wherein P is a protecting group and R ² is hydrogen can be prepared by cyclizing a compound of formula (XII) according to the following scheme:

In the above scheme, P is a protecting group, R ² is hydrogen, and A ¹ , B, R ¹ , R ³ , Y, n have the same definition as described above for the compound of formula (IIa). This reaction can be carried out using a Lawson reagent in a solvent such as pyridine at reflux or according to any other method known to those skilled in the art.

Compounds of formula (XII) can be prepared by reacting compounds of formula (XIII) with compounds of formula (XIV) according to the following scheme:

In the above scheme, P is a protecting group and A ¹ , R ¹ , R ² , R ³ and n have the same meanings as described above for the compound of formula (IIa). The reaction is carried out at low temperature using oxalyl chloride in a solvent such as dichloromethane to form an intermediate, acid chloride, which is subsequently followed by a compound of formula (XIV) in a solvent such as dichloromethane in the presence of a base such as triethylamine at room temperature. It may be carried out by reacting with a compound of, or may be carried out using any other reagents and reaction conditions known to those skilled in the art.

Compounds of formula (XIII) and (XIV) may be obtained commercially or prepared according to any conventional method known to those skilled in the art.

A.5. Compounds of formula (IIa) wherein P is a protecting group and R ² is hydrogen can be prepared by reducing the compound of formula (XV) according to the following scheme:

In the above scheme, P is a protecting group, R ² is hydrogen, and A ¹ , B, R ¹ , R ³ and n have the same definitions as described above for the compound of formula (IIa). This reaction can be carried out using hydrogen in the presence of a suitable catalyst such as platinum dioxide in a solvent such as acetic acid or using lithium triethylborohydride in tetrahydrofuran, or in any conventional method known to those skilled in the art. Can be carried out accordingly.

Compounds of formula (XV) may be prepared by cyclizing compounds of formula (XVI) according to the following scheme:

Wherein P is a protecting group, R ¹ is hydrogen, and A ¹ , B, R ¹ , R ³ and n have the same meanings as described above for the compound of formula (IIa). For example, this reaction can be carried out using Lawson's reagent in a solvent such as toluene at reflux temperature.

Compounds of formula (XVI) can be prepared by reacting compounds of formula (XIII) with compounds of formula (XVII) according to the following scheme:

In the above scheme, P, A ¹ , R ¹ , R ³ and n are defined as above. This reaction forms an acid chloride with oxalyl chloride in a solvent such as dichloromethane at low temperature, which is an intermediate, which is subsequently subjected to a steel such as sodium hydride at room temperature in a solvent such as N, N-dimethylformamide or dichloromethane. It can be reacted with a compound of formula (XVII) pretreated with a base or by using any other reagents and reaction conditions known to those skilled in the art.

Compounds of formula (XVII) may be obtained commercially or may be prepared according to any conventional method known to those skilled in the art.

A.6. Compounds of formula (II) wherein P is a protecting group and R ² is an acyl group are prepared according to the conventional methods known to those skilled in the art using the corresponding compounds of formula (II) wherein R ² is hydrogen. It can be prepared by reacting with an acid chloride or anhydride in a solvent such as.

A.7. A compound of formula (II) wherein P is H, Y is oxygen, B is a 5- to 8-membered heterocycloalkyl group containing a nitrogen atom, and R ² is linked to a nitrogen atom and is hydrogen; referred to as' a) can be prepared by deprotecting the compound of formula (II'b) according to the following scheme:

Wherein P is a protecting group such as benzyl, B is a 5-8 membered heterocycloalkyl group containing a nitrogen atom, and A ¹ , R ¹ , R ³ and n are the same definitions as described above for Formula (I) Has This reaction can be carried out using hydrogen as a reducing agent in a solvent such as acetic acid in the presence of a suitable catalyst such as palladium acetate, or can be carried out using any other reaction conditions known to those skilled in the art. Preferably, n is zero.

Compounds of formula (II′b) can be prepared by cyclizing the compounds of formula (XII) in the presence of a suitable activator such as titanium (IV) chloride, or using any other reagents and reaction conditions known to those skilled in the art. Can be prepared.

Some compounds of formula (II′b) may be prepared by reducing compounds of formula (XVIII) according to the following scheme:

In the above scheme, P is a protecting group such as benzyl and n is preferably 0 and A ¹ , R ¹ , R ³ and B have the same definitions as described above for the compound of formula (II′a). This reaction may be carried out using a reducing agent such as sodium borohydride in a solvent such as ethanol at temperatures in the range of 0 ° C. to 60 ° C., or may be carried out using any other reagents and reaction conditions known to those skilled in the art. . Preferably, n is zero.

Compounds of formula (XVIII) can be prepared by alkylating compounds of formula (XIX) according to the following scheme:

In the above scheme, P is a protecting group such as benzyl and A ¹ , R ¹ , R ³ and n have the same definitions as described above for the compound of formula (II′a). This reaction can be carried out using an alkylating agent such as benzyl bromide according to any conventional method known to those skilled in the art. Preferably, n is zero.

Compounds of formula (XIX) can be prepared by cyclizing compounds of formula (XX) according to the following scheme:

In the above scheme, P is a protecting group such as benzyl and A ¹ , R ¹ , R ³ and n have the same definitions as described above for the compound of formula (II′a). This reaction is carried out in triphenylphosphine in a solvent such as dichloromethane in the presence of a base such as triethylamine at room temperature according to the method described in Heuser, S. et al. Tetrahedron Lett., 2005, 46, 9001-9004. And hexachloroethane. Preferably, n is zero.

Compounds of formula (XX) can be prepared starting from the corresponding carboxylic acid (XIII) as described above for the preparation of compound (XVI) or according to any method known to those skilled in the art.

B. A ¹ is CH, X is sulfur, Y is sulfur and A, B, R ¹ , R ² , R ³ , m and n have the same definitions as described above for the compound of formula (I) Compounds of formula (I) may be prepared by reacting a compound of formula (XXI) with a compound of formula (VIII) according to the following scheme:

In the above scheme, A ¹ is CH, X is sulfur, Y is sulfur, A, B, R ¹ , R ² , R ³ , m and n have the same definition as described in the above formula, Hal is halogen And preferably a bromine atom.

This reaction is carried out in the presence of a solvent such as ethanol or iso-propanol at temperatures in the range from 50 ° C. to 100 ° C. or described in Ashton, WT et al. In Bioorg. Med. Chem. Lett. 2005, 15, 2253. Depending on the method, or by any other conventional method known to those skilled in the art.

Compounds of formula (XXI) can be prepared from compounds of formula (XXII) according to the following scheme:

In the above scheme, A and R ³ have the same definition as above. For example, this reaction can be carried out using a Lawson reagent in a solvent such as tetrahydrofuran at room temperature, or according to any other conventional method known to those skilled in the art.

Compounds of formula (XXII) can be prepared by ammonia decomposition of compounds of formula (XXI) according to the following scheme:

In the above scheme, A and R ³ have the same definition as above. This reaction can be carried out according to any other conventional method known to those skilled in the art.

Compounds of formula (XXIII) can be prepared by reacting compounds of formula (XXIV) with compounds of formula (III) according to the following scheme:

In the above schemes, A and R ³ have the same definitions as described above for the compound of formula (I).

This reaction may be carried out in the presence of a base such as sodium hydride in a solvent such as N, N-dimethylacetamide in an inert atmosphere at a temperature in the range of 50 ° C. to 80 ° C. It may be carried out under any other conditions and according to conventional methods known to those skilled in the art.

Compounds of formula (XXIV) may be obtained commercially or may be prepared according to any conventional method known to those skilled in the art.

C. X is oxygen, B is heteroaryl, R ² is H, m is 1, and A, R ¹ , R ³ and n have the same definition as described in formula (I) above Some compounds of can be prepared by cyclizing a compound of formula (XXV) wherein E is Cl or NH ₂ according to the following scheme:

This reaction can be carried out in the presence of Lawson's reagent in a solvent such as toluene at reflux (Y = S), or with hydrochloric acid in refluxed butanol, or according to any other method known to those skilled in the art.

Compounds of formula (XXV) can be prepared by aminocarbonylating compounds of formula (XXVI) according to the following scheme:

In the above scheme, A, R ¹ , R ³ and n have the same definition as described in the above formula. For example, this reaction can be carried out with molybdenum hexacarbonyl in a solvent such as anhydrous tetrahydrofuran under microwave irradiation according to the method described in Letavic M. et al. Tetrahedron Lett., 2007, 48, 2339-2343. In the presence of a carbon monoxide source, a suitable catalyst such as palladium acetate, and a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene, or in any other method known to those skilled in the art. Can be implemented accordingly.

Compounds of formula (XXVI) can be prepared by reacting compounds of formula (XXVII) with compounds of formula (III) according to the following scheme:

Wherein R ³ and A have the same definition as described above. This reaction may be carried out in an inert atmosphere at temperatures in the range of 50 ° C. to 80 ° C., for example in the presence of a base such as sodium hydride in a solvent such as N, N-dimethylacetamide, or any that is considered suitable to those skilled in the art. It may be carried out according to other conditions and conventional methods known to those skilled in the art.

Compounds of formula (XXVII) may be commonly available or may be prepared according to any conventional method known to those skilled in the art.

D. Some compounds of formula (I) may be prepared by standard conversion methods of other compounds of formula (I) to be:

Compounds of formula (la) in which R ² is hydrogen may be prepared using the corresponding formula (la) in which R ² is t-butoxycarbonyl (Boc) using an acid such as trifluoroacetic acid according to conventional methods known to those skilled in the art. Can be prepared by deprotecting the compound.

Compounds of formula (Ia) wherein R ² is an acyl group are prepared by reacting a corresponding compound of formula (Ia) wherein R ² is hydrogen with an acid chloride in the presence of a base such as triethylamine according to conventional methods known to those skilled in the art. Can be. This reaction also uses coupling agents, hydroxybenzotriazoles, activators such as EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), in a solvent such as dichloromethane, or to those skilled in the art It can be prepared using any other reagents and reaction conditions known in the art.

Compounds of formula (la) in which R ² is aminocarbonyl are those in which R ² is hydrogen in the presence of a base such as triethylamine in accordance with conventional methods known to those skilled in the art or at any other reaction conditions deemed appropriate to those skilled in the art. Phosphorus compounds of formula (la) may be prepared by reacting with isocyanates, or may be prepared according to conventional methods known to those skilled in the art.

Compounds of formula (la) in which R ² is aminosulfonyl can be prepared from compounds of corresponding formula (la) in which R ² is hydrogen. For example, this reaction can be carried out using aminosulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane. Alternatively, this reaction can be carried out according to the methods described in Beaudoin et al. In J. Org. Chem., 2003, 68, 1 15-119, or with minor modifications to these methods.

Compounds of formula (Ia) in which R ² is an alkyl group include bases such as potassium carbonate in the presence of catalytic amounts of sodium iodide according to conventional methods known to those skilled in the art for the corresponding compounds of formula (Ia) wherein R ² is hydrogen. Can be prepared by reacting with an alkyl halide. Alternatively, this reaction can be carried out by reductive amination with reducing agents such as sodium borohydride and carbonyl derivatives in a solvent such as ethanol according to conventional methods known to those skilled in the art.

R ² is di-alkylphosphonate compounds of formula (Ia) is, R ² is in a solvent such as methanol and water mixture of the compound of formula (Ia) corresponding to hydrogen at room temperature first, benzotriazole and formaldehyde and the reaction To form a benzotriazolyl intermediate. This intermediate was prepared according to the method described in Tiwari, RK et al. In Eur. J. Med. Chem., 2006, 41, 40-49 or with a slight modification of the zinc dibromide in a solvent such as dichloromethane. React directly with triethylphosphite in the presence of a Lewis acid such as

Compounds of formula (Ib) wherein R ² is carboxy can be prepared by hydrolyzing the corresponding compounds of formula (Ib) wherein R ² is alkoxycarbonyl according to conventional methods known to those skilled in the art.

Compounds of formula (Ia) wherein R ² is phosphonic acid can be prepared by dealkylation of the corresponding dialkylphosphonates of formula (Ia) in the presence of boro-trimethylsilane in a solvent such as acetonitrile, or It may be prepared according to any other method known to the.

Compounds of formula (Ia) in which R ² is cyclobutene-1,2-dione include compounds of formula (Ia) and 3,4-diisopropoxycyclobut- in which R ² is hydrogen in a solvent such as methanol. It may be prepared by reacting 3-ene-1,2-dione or may be prepared according to any other method known to those skilled in the art. Further synthetic modifications may include hydrolysis in the presence of an aqueous acid, or any other modification known to those skilled in the art.

In a further embodiment, the present invention relates to synthetic intermediates of formula (II)

Where

Y is S or O;

A ¹ , B, R ¹ , R ² , R ³ , m and n have the same definition as in the above formulas for compounds of formula (I).

In one particular embodiment, the present invention

A ¹ is CH;

B together with thiazole forms 4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

Y is S;

n is 0;

R ² is acetyl, aminoacetyl, aminocarbonyl, hydroxyacetyl, 2,3-dihydroxypropyl, (2S) -2,3-dihydroxypropyl, (2R) -2,3-dihydroxypropyl , 2-amino-2-oxoethyl, 3-hydroxycyclobutyl, 3-amino-3-oxopropanoyl, (5-methyl-2H-1,2,3-triazol-4-yl) carbonyl , 2-hydroxyethyl, (carboxymethoxy) acetyl, tetrahydro-2H-pyran-4-ylcarbonyl, [(1-aminocarbonyl) cyclopropyl] carbonyl, amino (oxo) acetyl, 2,3 -Dihydroxypropanoyl and 2-amino-3,4-dioxocyclobut-1-en-1-yl;

m is 1;

It relates to a compound of formula (II), wherein R ³ is hydrogen.

Examples of compounds of formula (II) according to the present invention include the following:

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol;

Tert-butyl 2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4H) -carboxylate;

2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [4,5-b] pyridin-5 (4H) -one;

4- (4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridin-2-yl) phenol;

4- (4-acetyl-5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azin-2-yl) phenol;

4- (4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridin-2-yl) phenol;

Ethyl 2- (4-hydroxyphenyl) -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5-carboxylate;

1- [2- (2-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone;

1- [2- (3-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone;

1- [2- (2,6-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanone; And

1- [2- (2,3-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanone.

In a further embodiment, the invention relates to synthetic intermediates of formula (III)

Where

A is a substituted or unsubstituted aliphatic or cyclic amino group linked to a cyclobutyl group via amino nitrogen;

X 'is methyl or bromine.

Examples of compounds of formula (III) according to the present invention include the following:

Cis-3-morpholin-4-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3- (4-isopropylpiperazin-1-yl) cyclobutyl 4-methylbenzenesulfonate;

Cis-3- (4,4-difluoropiperidin-1-yl) cyclobutyl 4-methylbenzenesulfonate;

Cis-3-pyrrolidin-1-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3-azpan-1-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-methylbenzenesulfonate;

Cis-3-thiomorpholin-4-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3-piperidin-1-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3- (2-methylpyrrolidin-1-yl) cyclobutyl 4-methylbenzenesulfonate;

Cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-bromobenzenesulfonate;

Cis-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl-4-bromobenzenesulfonate; And

Cis-3- (piperidin-1-yl) cyclobutyl-4-bromobenzenesulfonate.

According to one particular embodiment of the compound of formula (III), the A and O groups attached to cyclobutyl at the A-cyclobutyl-0 residue are in cis configuration.

In a further embodiment, the present invention relates to synthetic intermediates of formula (XXI):

Where

A is a substituted or unsubstituted aliphatic, or cyclic amino group linked to the cyclobutyl group via amino nitrogen;

R ³ is hydrogen, C _{1 -6} alkyl, halogen, or C _{1 -6} alkoxy.

An example of a compound of formula (XXI) is 4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] benzenecarbothioamide.

In another embodiment, the present invention relates to a synthetic intermediate of formula (XXII):

Where

A is a substituted or unsubstituted aliphatic or cyclic amino group linked to a cyclobutyl group via amino nitrogen;

R ³ is hydrogen, C _{1 -6} alkyl, halogen or C _{1 -6} alkoxy.

An example of a compound of formula (XXII) is 4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] benzoic acid.

In another embodiment, the present invention relates to a synthetic intermediate of formula (XXIII):

Where

A is a substituted or unsubstituted aliphatic or cyclic amino group linked to a cyclobutyl group via amino nitrogen;

R ³ is hydrogen, C _{1 -6} alkyl, halogen or C _{1 -6} alkoxy.

An example of a compound of formula (XXIII) is 4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] benzoic acid.

In another embodiment, the present invention relates to a synthetic intermediate of formula (XXV):

Where

A is a substituted or unsubstituted aliphatic, or cyclic amino group linked to a cyclobutyl group via amino nitrogen;

R ¹ is sulfonyl, amino, substituted or non-unsubstituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, unsubstituted or unsubstituted C _{2 -6-alkynyl,} optionally substituted aryl, which is unsubstituted or heteroaryl, optionally substituted non-substituted C _{3 -8} cycloalkyl, substituted or non-3- to 8-membered heterocycloalkyl, acyl, optionally substituted non-substituted C _{1 -6} alkyl, aryl, optionally substituted that is not C _{1 -6-alkyl-heteroaryl,} substituted or unsubstituted C _{2 -6} alkenyl aryl, substituted or unsubstituted C _{2 -6} - alkenyl heteroaryl, substituted or unsubstituted C _{2 -6} - alkynyl aryl, optionally substituted C _{2 -6} - alkynyl heteroaryl, optionally substituted C _{1 -6} alkyl, cycloalkyl, optionally substituted C _{1 -6} alkyl, heterocycloalkyl, optionally substituted C _2-6 -alkenyl cycloalkyl, substituted or unsubstituted C _{2 -6-alkenyl} heterocycloalkyl, substituted or unsubstituted C _{2 -6-alkynyl} cycloalkyl, substituted or unsubstituted C _{2 -6-alkynyl} heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6} alkyl carboxy, optionally substituted C _{1 -6} alkyl, acyl, substituted or unsubstituted aryl acyl, substituted or unsubstituted heteroaryl aryl acyl, substituted or unsubstituted C _{3 -8} - (hetero) cycloalkyl acyl, that is optionally substituted with C _{1 -6-alkyl} acyloxy, substituted or unsubstituted C _{1 -6} alkyl, alkoxy, optionally substituted C _1-6 alkyl alkoxycarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} optionally substituted C _{1 -6} alkyl, acyl, acylamino, acylamino carbonate , Ureido, optionally substituted C _{1 -6} alkyl ureido, substituted or unsubstituted C _1-6 alkyl carbamate, substituted or unsubstituted C _{1 -6} alkylamino, optionally substituted C _{1 -6} alkylsulfonyloxy, optionally substituted C _{1 -6} alkyl sulfonyl, optionally substituted C _{1 -6} alkyl sulfinyl, optionally substituted C _{1 -6} alkyl sulfanyl, substituted or unsubstituted It is C _{1 -6-alkyl} sulfonylamino, aminosulfonyl, optionally substituted C _{1 -6} alkyl aminosulfonyl, hydroxy, optionally substituted C _{1 -6} alkyl, hydroxy, phosphonate, substituted or unsubstituted C _{1 -6} alkyl phosphonate, optionally substituted C _{1 -6} alkyl phosphono, include halogen, cyano, carboxy, oxo and thioxo, or is selected from the group consisting therefrom;

n is 0, 1, 2 or 3;

R ³ is hydrogen, C _{1 -6} alkyl, halogen, or C _{1 -6} alkoxy.

An example of a compound of formula (XXV) is N- (4-chloropyridin-3-yl) -4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] benzamide.

Examples of synthetic intermediates used to synthesize the compounds of formula (I) according to the invention include the following:

3-morpholin-4-ylcyclobut-2-en-1-one;

3- (4-isopropylpiperazin-1-yl) cyclobut-2-en-1-one;

3- (4,4-difluoropiperidin-1 -yl) cyclobut-2-en-1-one;

3-azane-1-ylcyclobut-2-en-1-one;

3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobut-2-en-1-one;

3-thiomorpholin-4-ylcyclobut-2-en-1-one;

Cis-3-morpholin-4-ylcyclobutanol;

Cis-3- (4-isopropylpiperazin-1-yl) cyclobutanol;

Cis-3- (4,4-difluoropiperidin-1-yl) cyclobutanol;

Cis-3-pyrrolidin-1-ylcyclobutanol;

Cis-3-azane-1-ylcyclobutanol;

Cis-3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobutanol;

Cis-3-thiomorpholin-4-ylcyclobutanol;

Cis-3-piperidin-1-ylcyclobutanol;

Cis-3-morpholin-4-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3- (4-isopropylpiperazin-1-yl) cyclobutyl 4-methylbenzenesulfonate;

Cis-3- (4,4-difluoropiperidin-1-yl) cyclobutyl 4-methylbenzenesulfonate;

Cis-3-pyrrolidin-1 -ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3-azpan-1-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-methylbenzenesulfonate;

Cis-3-thiomorpholin-4-ylcyclobutyl 4-methylbenzenesulfonate;

Cis-3-piperidin-1 -ylcyclobutyl 4-methylbenzenesulfonate;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol;

Tert-butyl 2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4H) -carboxylate;

3-methyl-1- (morpholin-4-ylsulfonyl) -1H-imidazole-3-ium trifluoromethanesulfonate;

Tert-butyl {2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thia Zolo [5,4-c] pyridin-5 (4H) -yl] ethyl} carbamate;

Methyl 3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, 4-c] pyridin-5 (4H) -yl] propanoate;

3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] cyclobut-2-en-1-one;

2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [4,5-b] pyridin-5 (4H) -one;

4- (4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridin-2-yl) phenol;

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] Pyridine;

4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] benzoic acid;

4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] benzamide;

4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] benzenecarbothioamide;

4- (benzyloxy) -N- (2-oxoasepan-3-yl) benzamide;

2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine hydrochloride;

4-acetyl-2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine;

4- (4-acetyl-5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azin-2-yl) phenol;

4- (benzyloxy) -N- (4-hydroxypyridin-3-yl) benzamide;

2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine;

5-benzyl-2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine-5-ium;

5-benzyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine;

4- (4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenyl acetate;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol;

4- (benzyloxy) -N- (4-chloropyridin-3-yl) benzamide;

2- [4- (benzyloxy) phenyl] [1,3] thiazolo [4,5-c] pyridine;

2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine;

5-acetyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridin-2-yl) phenol;

Methyl 3-bromo-4-hydroxycyclopentanecarboxylate;

Methyl 3-bromo-4-oxocyclopentanecarboxylate;

Ethyl 2- (4-hydroxyphenyl) -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5-carboxylate;

Ethyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5 Carboxylates;

1- [trans-3- (4-iodophenoxy) cyclobutyl] piperidine;

N- (4-chloropyridin-3-yl) -4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] benzamide;

3- (4-cyclopentylpiperazin-1-yl) cyclobut-2-en-1-one;

3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobut-2-en-1-one;

3- (2-methylpyrrolidin-1-yl) cyclobut-2-en-1-one;

Cis-3- (4-cyclopentylpiperazin-1-yl) cyclobutanol;

Cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutanol;

Cis-3- (2-methylpyrrolidin-1-yl) cyclobutanol;

Cis-3- (2-methylpyrrolidin-1-yl) cyclobutyl 4-methylbenzenesulfonate;

2- (benzyloxy) -1- [2- (4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} phenyl) -6,7-dihydro [1,3] thia Zolo [4,5-b] pyridin-4 (5H) -yl] ethanone;

2-fluoro-4-hydroxybenzenecarbothioamide;

3-fluoro-4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -3-fluorophenyl acetate;

1- [2- (2-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone;

3-fluoro-4-methoxybenzenecarbothioamide;

2,6-difluoro-4-methoxybenzenecarbothioamide;

2,3-difluoro-4-methoxybenzenecarbothioamide;

2- (3-fluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

2- (2,6-difluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

2- (2,3-difluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;

1- [2- (3-fluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone;

1- [2- (2,6-difluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanone;

1- [2- (2,3-difluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanone;

1- [2- (3-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone;

1- [2- (2,6-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanone;

1- [2- (2,3-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanone;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -2-fluorophenyl acetate;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -3,5-difluorophenyl acetate;

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -2,3-difluorophenyl acetate;

N- (2-oxoasepan-3-yl) -4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} benzamide;

N- (3-aminopyridin-4-yl) -4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} benzamide;

Cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-bromobenzenesulfonate;

Cis-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl 4-bromobenzenesulfonate;

Cis-3- (piperidin-1-yl) cyclobutyl 4-bromobenzenesulfonate;

N, N-dimethyl-1- {trans-3- [4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy] Cyclobutyl} pyrrolidin-3-amine;

2- (4-{[trans-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine;

2- (4-{[trans-3- (2-methylpyrrolidin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine;

1- [2- (4-{[trans-3- (2-methylpyrrolidin-1-yl) cyclobutyl] oxy} phenyl) -6,7-dihydro [1,3] thiazolo [5, 4-c] pyridin-5 (4H) -yl] ethanone; And

2- (4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5- c] pyridine.

The compounds of formula (I) and pharmaceutically acceptable salts thereof according to the invention are newly found to be useful for a variety of medical diseases.

For example, the compounds according to the invention can be used for mild cognitive impairment, Alzheimer's disease, learning and memory disorders, cognitive impairment, attention deficit disorder, attention deficit hyperactivity disorder, Parkinson's disease, schizophrenia, dementia, depression, epilepsy, seizures, convulsions Useful for treating and preventing diseases or conditions of the central nervous system, including sleep / wake and wake / bound disorders such as hypersomnia and narcolepsy, pain and / or obesity.

In addition, the compounds according to the invention may be useful for the treatment of epilepsy, seizures or convulsions, alone or in combination with antiepileptic drugs (AED). It is known in the literature that the combination of H ₃ receptor ligand and AED may produce additional synergistic effects on efficacy with reduced side effects such as reduced insomnia, sedation or cognitive problems.

In addition, the compounds of formula (I), alone or in combination with histamine H ₁ antagonists, may also be useful for the treatment of upper airway allergic disorders.

In one specific embodiment of the invention, the compound of formula (I), alone or in combination with a muscarinic receptor ligand and in particular a muscarinic M ₂ antagonist, for the treatment of cognitive disorders, Alzheimer's disease, and attention deficit hyperactivity disorder May be useful for

In particular, compounds of formula (I) that exhibit NO-donor properties, alone or in combination with nitric oxide (NO) release agents, may be useful for treating cognitive dysfunction.

Compounds of formula (I) may also be useful for the treatment and prevention of multiple sclerosis (MS).

Usually, compounds of formula (I) can be used for the treatment and prevention of all types of disorders related to cognition.

In one embodiment, the compounds of formula (I) can be used to treat and prevent cognitive dysfunction in diseases such as mild cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, Down's syndrome, and to treat attention deficit hyperactivity disorder have.

In another embodiment, the compound of formula (I) also treats and prevents psychosis, such as schizophrenia; Or to treat an eating disorder such as obesity; Or to treat inflammatory and pain disorders; Or to treat anxiety, stress and depression; Or to treat cardiovascular disorders such as myocardial infarction; Or to treat and prevent multiple sclerosis (MS).

Pain disorders include neuropathic pain, such as those associated with diabetic neuropathy, post shingles neuralgia, tertiary neuralgia, posttraumatic peripheral neuropathy, annular pain, cancer, and neuropathy induced by treatment with anti-neoplastic agents; Pain due to nerve damage associated with demyelinating diseases such as multiple sclerosis, neuropathy associated with HIV; Pain after surgery; Inflammatory pain, such as associated with pericorneal pain, colic (pain relief during labor or after caesarean surgery), visceral pain, rheumatoid arthritis; Low back pain / sciatic neuralgia; Heterogeneous pain, such as tingling syndrome, fibromyalgia; Complex pain syndrome (CRPS), and chronic pain associated with chronic muscle pain, including but not limited to those associated with back injury.

In one particular embodiment, the compounds of formula (I) can be used to treat and prevent neuropathic pain.

In one embodiment, the compounds of formula (I) according to the invention can be used as medicaments.

In another embodiment, the compounds of formula (I) according to the invention are used for the treatment of mild cognitive impairment, Alzheimer's disease, learning and memory disorders, attention deficit hyperactivity disorder, Parkinson's disease, schizophrenia, dementia, depression, epilepsy, seizures, convulsions, Treatment or prevention of sleep / wake disorders, cognitive dysfunction, narcolepsy, hypersomnia, obesity, upper airway allergic disorder, Down syndrome, anxiety, stress, cardiovascular disorders, inflammation, pain disorders, especially neuropathic pain or multiple sclerosis Can be used for

In one particular embodiment, the compounds of formula (I) according to the invention can be used for the treatment of mild cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, Down syndrome, and for the treatment of attention deficit hyperactivity disorder. .

In a further embodiment, the present invention is directed to mild cognitive impairment, Alzheimer's disease, learning and memory disorders, attention deficit hyperactivity disorder, Parkinson's disease, schizophrenia, dementia, depression, epilepsy, seizures, convulsions, sleep / wake disorders, cognition Used to prepare drugs for treating and preventing dysfunction, narcolepsy, hypersomnia, obesity, upper respiratory allergic disorders, Down syndrome, anxiety, stress, cardiovascular disorders, inflammation, pain disorders, especially neuropathic pain or multiple sclerosis To a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of said compound.

In another embodiment, the invention is used in the manufacture of a medicament for the treatment of mild cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, cognitive dysfunction in diseases such as Down syndrome, and treatment of attention deficit hyperactivity disorder. The use of a compound of (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of said compound.

The method of the present invention comprises administering to a mammal (preferably a human) suffering from the above-mentioned conditions or diseases in an amount sufficient to alleviate or prevent said diseases or conditions.

The compound is conveniently administered in any suitable unit dosage form, including but not limited to, containing 3 to 3000 mg of active ingredient per unit dosage form.

The term "treatment" as used herein includes therapeutic and prophylactic treatments.

By "therapeutic" is meant efficacy in treating the present symptomatic episode of the disorder or condition.

By "prophylactic" is meant the prevention of the onset or recurrence of a disease or condition.

As used herein, the term “cognitive impairment” refers to a disturbance of cognitive abilities, including perception, learning, and reasoning, or in other respects a physiological (mental / nerve) process that selectively acquires, stores, and recalls information. do.

As used herein, the term “attention deficit hyperactivity disorder” (ADHD) refers to a problem with carelessness, hyper-behavioral, impulse, or a combination thereof. For these problems diagnosed with ADHD, they must be outside the normal range for the child's age and development. The term "attention deficit disorder" (ADD) is also generally used for the same disease.

As used herein, the term “Alzheimer's disease” (AD) refers to a progressive, neurodegenerative disease characterized by an entangled bundle of fibers (entanglement of nerve fibers) and abnormal clumps (amyloid plaques) composed of proteins that are incorrectly located in the brain. it means. Age is the most important risk factor for AD; The number of patients with this disease doubles every five years in ages 65 and older. Three genes have been identified that cause early onset (family) AD. Another genomic variation that causes excessive accumulation of amyloid proteins is age-related (sporadic) AD. Symptoms of AD include memory loss, language degeneration, impaired ability to mentally manipulate visual information, lack of judgment, confusion, restlessness, and mood changes. Eventually, AD destroys cognitive, personality and role-playing abilities. Early symptoms of AD, including forgetfulness and lack of concentration, are often missed because they resemble natural signs of aging.

As used herein, the term “Parkinson's disease” (PD) refers to a group of conditions called motor disorders that are the result of damage to dopamine producing brain cells. Four major symptoms of PD include tremors or tremors in the hands, arms, legs, jaw, and face; Stiffness or stiffness of the limbs and torso; Slow movement or movement; And postural instability or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking or completing other simple tasks. PD usually affects people over 50. Early symptoms of PD are subtle and progressive. In some people, the disease progresses more quickly than in others. As the disease progresses, the shaking or tremors that occur in the majority of PD patients may begin to interfere with daily life. Other symptoms include depression and other emotional changes; Difficulty in swallowing, chewing and speaking; Problems with urination or constipation; Skin problems; And sleep disturbances.

As used herein, the term “down syndrome” refers to a chromosomal abnormality that usually results from excessive replication of the 21st chromosome. This syndrome usually causes, but not always, mental retardation and other symptoms. The term "mental retardation" refers to a sub-generic general intelligence with a related deficit in adaptive behavior appearing before age 18.

As used herein, the term "mild cognitive impairment" refers to the cognitive impairment of the metastatic stage between normal aging and early Alzheimer's disease. This specifically refers to the clinical condition of an individual who exhibits impaired memory but performs well and does not meet clinical criteria for dementia.

The term "obesity" as used herein refers to a body mass index (BMI) of greater than 30 kg / m 2.

As used herein, the term “dementia” refers to a group of symptoms that include progressive impairment of brain function. The American Geriatric Institute refers to dementia as a state of declining intellectual ability, especially memory. An individual will have trouble carrying out what he or she could do, such as keeping a checkbook, driving a car safely or preparing a meal. He or she will often have trouble finding the right words and may be embarrassed if too much is given to do right away. People with dementia may also change their personality, become aggressive, become overly delusional, or suffer from depression.

As used herein, the term “schizophrenia” refers to a group of psychosis characterized by disturbances in thought, perception, attention, emotions, behavior, and conversation that last six months or longer. This disease makes it difficult for patients to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses to others, and to act normally in social situations.

As used herein, the term “anxiety” means anxiety or fear. Anxiety is often accompanied by physical symptoms including cramps or tremors, muscle tension, headache, sweating, dry mouth, difficulty swallowing and / or abdominal pain.

As used herein, the term "narcolepsy" refers to lifespan disorders associated with uncontrollable sleep and frequent daytime sleep.

The term "depression" as used herein refers to mood disturbances and is characterized by a loss of interest or enjoyment in normal daily life. A person with depression can feel depressed for weeks, months, or even years. Some of the following symptoms may be symptoms of depression: depression, persistent sad, anxious and empty mood; Feeling of disrespect and pessimism; Guilt, worthlessness, hopelessness; Lack of interest or enjoyment in past hobbies and activities, including sex; Reduced motivation, fatigue, feeling of falling; Difficulty in concentration, memory, and decision making; Insomnia, early morning awakening or excessive sleep; Appetite and / or weight loss or overeating and weight gain; Death or suicidal thoughts; Attempt to commit suicide; Restlessness, insensitivity; Persistent physical symptoms that do not respond to treatment, such as headaches, digestive problems, and chronic pain.

The term “epilepsy” as used herein refers to a brain disorder in which neuronal cells or neuronal bundles sometimes abnormally signal in the brain. In epilepsy, normal patterns of neuronal activity are disturbed, causing unfamiliar sensations, emotions, and behaviors, or sometimes cramps, muscle spasms, and impaired perception. Epilepsy is a disease with a number of possible causes. Anything that interferes with the normal pattern of neuronal activity, from disease to brain damage to abnormal brain development, can cause seizures. Epilepsy can progress due to abnormal brain wiring, an imbalance of nerve signaling chemicals called neurotransmitters, or some combination of these factors. Seizures do not necessarily mean that the individual has epilepsy. Only if the individual has more than one seizure he or she is considered to have epilepsy.

As used herein, the term “seizure” refers to a temporary change in behavior due to dizzy, concurrent and rhythmic firing of a brain neuronal population.

As used herein, the term “migraine” means a disease characterized by a recurrent onset of headache that varies widely in intensity, frequency, and duration. Pain in headache due to migraine is described as a violent wave or vibration in one area of the head. This is often accompanied by sensitivity to light and sound, nausea and vomiting. Some individuals may predict the development of migraine headaches because this is preceded by "prognosis", which is a visual disturbance that manifests as flashes, dizziness, or temporary vision loss. People with migraines tend to have recurrent onset caused by decreased appetite or lack of sleep, light exposure or hormonal irregularities (only in women). Anxiety, stress or relaxation after stress can also be a cause. For many years, scientists believed that migraine headaches were involved in the expansion and contraction of blood vessels in the head. Researchers now believe that migraines are caused by genetic abnormalities in genes that control the activity of specific cell populations in the brain. The International Headache Institute (IHS, 1988) classifies migraine headaches as a major type of migraines (traditional migraine headaches) and migraine-free migraine headaches (common migraine headaches).

As used herein, the term "multiple sclerosis (MS)" refers to a chronic disease in the central nervous system in which progressive destruction of myelin occurs in part through the brain or spinal cord or both, disrupting nerve pathways. As nerves become more and more involved, patients experience gradual obstruction in functions regulated by the nervous system such as vision, speech, gait, writing and memory.

The activity at any of the aforementioned indications can be measured in the design of a general clinical trial and / or by conducting a suitable clinical trial in a manner known to those skilled in the art for the particular indication.

In the treatment of a disease, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in an effective daily dose and may be administered in the form of a pharmaceutical composition.

Accordingly, another embodiment of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

To prepare a pharmaceutical composition according to the invention, at least one compound of formula (I) or a pharmaceutically acceptable salt thereof is intimately mixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical combination techniques known to those skilled in the art. .

Suitable diluents and carriers can take various forms depending on the desired route of administration, such as oral, rectal, parenteral or nasal.

Pharmaceutical compositions comprising a compound according to the invention can be administered, for example, orally, parenterally, ie intravenously, intramuscularly or subcutaneously, in meninges, by inhalation or intranasally.

Pharmaceutical compositions suitable for oral administration may be solid or liquid, which may, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gums and the like.

To this end, the active ingredient may be admixed with an inert diluent or a nontoxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, such pharmaceutical compositions may also contain binders such as microcrystalline cellulose, tragacanth gum or gelatin, disintegrants such as alginic acid, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or Saccharin, or colorants or flavoring agents such as peppermint or methyl salicylate.

The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are generally in the conventional form, such as aqueous or oily solutions or suspensions contained in ampoules, disposable syringes, glass or plastic vials or infusion containers.

In addition to the active ingredient, such solutions or suspensions may optionally contain sterile diluents such as water for injection, physiological saline solution, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as as Corbic acid or sodium bisulfite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetate, citrate or phosphate, and osmotic pressure regulators such as sodium chloride or dextrose.

Such pharmaceutical forms are prepared using methods commonly used by formulators.

The amount of active ingredient in the pharmaceutical composition may be within a wide range of concentrations, depending on various factors such as the sex, age, weight and medical condition of the patient, and the method of administration. Accordingly, the amount of the compound of formula (I) in the composition for oral administration is at least 0.5% by weight and may be up to 80% by weight relative to the total weight of the composition.

In a preferred oral composition, the daily dose is in the range of 3 to 3000 mg of the compound of formula (I).

In compositions for parenteral administration, the amount of compound of formula (I) present is at least 0.5% by weight and may be up to 33% by weight relative to the total weight of the composition. In a preferred parenteral composition, the dosage unit is in the range of 3 to 3000 mg of the compound of formula (I).

Daily doses may be included in a wide range of dosage units of the compound of formula (I), which are generally in the range of 3 to 3000 mg. However, it should be understood that specific dosages may be tailored to the specific case that depends on individual requirements at the discretion of the attending physician.

The following examples illustrate how the compounds included in formula (I) can be synthesized. They are provided for purposes of illustration only and are not intended to limit the invention in any way and should not be so interpreted. Those skilled in the art will appreciate that general modifications and variations can be made in the following examples without departing from the spirit or scope of the invention.

NMR spectra are Linux workstations running on XWIN NMR 3.5 software and a Bruker ADVANCE 400 NMR spectrometer with 5 mm inverse ¹ H / BB probehead, or SG Fuel running on XWIN NMR 2.6 software. , And a Bruker DRX 400 NMR with ¹ H / ¹³ C / ¹⁹ F triple probehead in 5 mm inverse geometry. Compounds were studied in d ₆ -dimethylsulfoxide (or d ₃ -chloroform) solution at a probe temperature of 313 K or 300 K and at a concentration of 10 mg / ml. This device was locked against the doublet signal of d ₆ -dimethylsulfoxide (or d ₃ -chloroform). Chemical shifts are expressed in ppm in the down zone from TMS (tetramethylsilane) taken as internal standard.

HPLC analysis was performed using one of the following systems:

-Agilent 1100 Series HPLC System with INERTSIL ODS 3 C18, DP 5 μm, 250 × 4.6 mm column. The gradient is from 100% solvent A (acetonitrile, water, phosphoric acid (5/95 / 0.001, v / v / v)) to 100% solvent B (acetonitrile, water, phosphoric acid (95/5 / 0.001, v) within 6 minutes. / v / v)) and maintained at 100% B for 4 minutes. The flow rate was set at 2.5 ml / min. Chromatography was performed at 35 ° C.

HP Waters Symmetry C18, HP 1090 series HPLC system equipped with 250 × 4.6 mm column. The gradient is from 100% solvent A (methanol, water, phosphoric acid (15/85 / 0.001 M, v / v / M)) to 100% solvent B (methanol, water, phosphoric acid (85/15 / 0.001 M, v) within 10 minutes. / v / M)) and maintained at 100% B for 10 minutes. Flow rate was set to 1 ml / min. Chromatography was performed at 40 ° C.

Measurements by mass spectrometer in LC / MS mode were performed as follows:

HPLC  Condition

The analysis was carried out using a Waters Alliance HPLC system equipped with an Inertsyl ODS 3, DP 5 μm, 250 × 4.6 mm column.

The gradient is from 100% solvent A (acetonitrile, water, trifluoroacetic acid (10/90 / 0.1, v / v / v)) to 100% solvent B (acetonitrile, water, trifluoroacetic acid (90 10 / 0.1, v / v / v)) and was maintained at 100% B for 4 minutes. The flow rate was set at 2.5 ml / min and a 1/25 split was used just before the API source.

MS  Condition

Samples were dissolved in acetonitrile / water, 70/30, v / v at a concentration of about 250 μg / ml. API spectra (+ or −) were performed using a FINIGAN LCQ ion trap mass spectrometer. The APCI source was operated at 450 ° C. and the capillary heater was operated at 160 ° C. The ESI source was operated at 3.5 kV and the capillary heater was operated at 210 ° C.

Measurements by mass spectrometer in DIP / EI mode were performed as follows: Samples were vaporized by heating the probe from 50 ° C. to 250 ° C. in 5 minutes. El (electron shock) spectra were recorded using a Finigan TSQ 700 tandem quadrupole mass spectrometer. The source temperature was set at 150 ° C. In the GC / MS mode, the TSQ 700 tandem quadrupole mass spectrometer (Pinigan MAT), a DB-5MS fused silica column (15 mx 0.25 mm ID, 1 μm), manufactured by J. and W. Scientific, equipped with a split / non-split mode injector This was performed using this equipped gas chromatography model 3400 (Varian). Helium (purity 99.999%) was used as the carrier gas. The injector (CTC A200S autosampler) and transfer line were operated at 290 ° C and 250 ° C, respectively. Samples (1 μl) were injected in undivided mode and the oven temperature was programmed as follows: 50 ° C. for 5 minutes, 280 ° C. (23 ° C./min) increase, and hold for 10 minutes. The TSQ 700 spectrometer was operated in electron impact (El) or chemical ionization (Cl / CH ₄ ) mode (mass range 33-800, scan time 1.00 sec). The source temperature was set at 150 ° C.

Specific rotations were recorded on a Perkin-Elmer 341 polarizer. Rotation angles were recorded at 589 nm and 25 ° C. for a 1% solution in methanol.

Melting points were measured on a Buchi 535 or 545 Totoli-type melt system and were not corrected to the starting temperature on a Perkin Elmer DSC 7.

Separation by preparative chromatography was carried out using a Novasep axial compression column (80 mm id) with silica gel 60 Merck at a flow rate of 70 to 150 ml / min, particle size 15-40 μm, reference 1.15111. It was run on 9025. The amount of silica gel and solvent mixture is described in a separate procedure.

Separation by preparative chiral chromatography using DAICEL using an in-house build of lower alcohol and C5 to C8 linear, branched or cyclic alkanes at ± 350 ml / min. ) Was performed on a Chiralpak AD 20 μm, 100 * 500 mm column. Solvent mixtures are described in separate procedures.

Example 1. 5-acetyl-2- {4-[(trans-3-morpholin-4 -ylcyclobutyl ) oxy ] phenyl } -4,5,6,7- tetrahydro [1,3] ti Synthesis of Azolo [5,4-c] pyridine 8 .

1.1 Synthesis of 3-morpholin-4-ylcyclobut-2-en-1-one a2 .

Trifluoroacetic acid (0.924 ml, 12.43 mmol, 1.1 eq) was added N-cyclohexylcyclohexaneaminium 3-oxocyclobut-1-ene-1-oleate a1 in dioxane (15 ml) over 10 minutes. (3 g, 1 1.30 mmol, 1 eq) was added to the stirred suspension. After 12 hours at room temperature, the resulting suspension was filtered and washed with dioxane (3 ml). The filtrate was then stirred and treated with morpholine (1.29 ml, 14.69 mmol, 1.3 eq) while maintaining the temperature below 20 ° C. throughout adding water bath (20 min). The mixture was stirred at rt overnight. Dioxane was then removed under reduced pressure. The resulting oil (2.4 g) was purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 98: 1.8: 0.2 followed by 97: 2.7: 0.3) to give 1.1 g of 3-morpholine-4- Ilcyclobut-2-en-1-one a2 was obtained. Yield 64%.

LC-MS (MH ⁺ ): 154.

The following compounds can be synthesized in the same way:

a3 3- (4-isopropylpiperazin-1-yl) cyclobut-2-en-1-one LC-MS (MH ⁺ ): 195 a4 3- (4,4-difluoropiperidin-1-yl) cyclobut-2-en-1-one LC-MS (MH ⁺ ): 188 a5 3-pyrrolidin-1-ylcyclobut-2-en-1-one LC-MS (MH ⁺ ): 138 a6 3-azane-1-ylcyclobut-2-en-1-one LC-MS (MH ⁺ ): 166 a7 3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobut-2-en-1-one LC-MS (MH ⁺ ): 181 a8 3-thiomorpholin-4-ylcyclobut-2-en-1-one LC-MS (MH ⁺ ): 170 a9 3-piperidin-1-ylcyclobut-2-en-1-one ¹ H NMR (CDCl ₃ ) δ: 4.47 (s, 1 H), 3.22 (m, 4 H), 2.95 (s, 2 H), 1.53 (m, 6 H) a70 3- (4-cyclopentylpiperazin-1-yl) cyclobut-2-en-1-one LC-MS (MH ⁺ ): 221 a71 3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobut-2-en-1-one LC-MS (MH ⁺ ): 181 a72 3- (2-methylpyrrolidin-1-yl) cyclobut-2-en-1-one LC-MS (MH ⁺ ): 152

1.2 Synthesis of cis-3-morpholine-ylcyclobutanol a10 .

A solution of 3-morpholin-4-ylcyclobut-2-en-1-one a2 (1.1 g, 7.18 mmol, 1 eq) in ethanol (18 ml) was dissolved in sodium borohydride (0.951 g, 25.13 mmol, 3.5 eq) parts. At the end of the addition, the mixture was stirred at 50 ° C. for 12 h, cooled to 20 ° C. and treated with acetone (2.3 ml). The solvent was removed under reduced pressure leaving a yellow solid which was dissolved in dichloromethane. The organic layer was filtered over celite and concentrated under reduced pressure to yield 1.5 g of cis-3-morpholin-ylcyclobutanol a10 as a yellow oil which was used directly in the next step without further purification.

Yield: 100%.

LC-MS (MH ⁺ ): 158.

The following compounds can be synthesized in the same way:

a11 Cis-3- (4-isopropylpiperazin-1-yl) cyclobutanol LC-MS (MH ⁺ ): 199 a12 Cis-3- (4,4-difluoropiperidin-1-yl) cyclobutanol LC-MS (MH ⁺ ): 192 a13 Cis-3-pyrrolidin-1-ylcyclobutanol LC-MS (MH ⁺ ): 142 a14 Cis-3-azane-1-ylcyclobutanol LC-MS (MH ⁺ ): 170 a15 Cis-3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobutanol LC-MS (MH ⁺ ): 185 a16 Cis-3-thiomorpholin-4-ylcyclobutanol LC-MS (MH ⁺ ): 174 a17 Cis-3-piperidin-1-ylcyclobutanol ¹ H NMR (CDCl ₃ ) δ: 3.81 (m, 3 H), 2.38 (m, 2 H), 2.06 (m, 4 H), 1.69 (m, 2 H), 1.43 (m, 4 H), 1.29 (bs, 2 H) a73 Cis-3- (4-cyclopentylpiperazin-1-yl) cyclobutanol LC-MS (MH ⁺ ): 225 a74 Cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutanol LC-MS (MH ⁺ ): 185 a75 Cis-3- (2-methylpyrrolidin-1-yl) cyclobutanol LC-MS (MH ⁺ ): 156

1.3 Synthesis of cis-3-morpholin- ylcyclobutyl 4-methylbenzenesulfonate a18 .

A solution of cis-3-morpholin-ylcyclobutanol a10 (1.5 g, 9.54 mmol, 1.0 eq) and N-methylimidazole (0.84 ml, 10.50 mmol, 1.1 eq) in ethyl acetate (15 ml) was prepared. Treated with p-toluenesulfonyl chloride (2.0 g, 10.50 mmol, 1.1 eq). The mixture was stirred at 20 ° C. for 1 hour. The mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield 2.6 g of yellow oil. This oil was purified by flash chromatography on silica gel (dichloromethane / methanol 100: 0 to 90:10) to give 0.61 cis-3-morpholin-4- ylcyclobutyl 4-methylbenzenesulfonate a18 as an orange oil. Obtained.

Yield 21%.

LC-MS (MH ⁺ ): 312.

The following compounds can be synthesized in the same way:

a19 Cis-3- (4-isopropylpiperazin-1-yl) cyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 353 a20 Cis-3- (4,4-difluoropiperidin-1-yl) cyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 346 a21 Cis-3-pyrrolidin-1-ylcyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 296 a22 Cis-3-azpan-1-ylcyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 324 a23 Cis-3-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 339 a24 Cis-3-thiomorpholin-4-ylcyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 328 a25 Cis-3-piperidin-1-ylcyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 310 a76 Cis-3- (2-methylpyrrolidin-1-yl) cyclobutyl 4-methylbenzenesulfonate LC-MS (MH ⁺ ): 310

1.4 Synthesis of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol a28 .

1.4.1 Synthesis of 1-acetyl-3- bromopiperidin -4-one a27

Chloroform (10 ml) bromine (12.24 g, 76.60 mmol, 1.1 eq) 1- acetyl-piperidine-4-one a26 (9.83 g in chloroform (160 ml) a solution of from 0 ℃, 69.63 mmol, 1 eq of Dropwise). The mixture was left to warm to 20 ° C. The white solid formed was filtered and washed with water to yield 14.9 g of 1-acetyl-3- bromopiperidin -4-one a27 .

Yield: 97%.

GC-MS (M ⁺ .): 219/221.

14.2 Synthesis of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol a28 .

A solution of 1-acetyl-3-bromopiperidin-4-one a27 (14.37 g, 65.27 mmol, 1 eq) in isopropanol (220 ml) was purified with 4-hydroxybenzenecarbothioamide (10 g, 65.27 mmol, 1 eq) and the mixture was stirred at 60 ° C. for 2 hours. The mixture was then concentrated under reduced pressure. The crude product was dissolved in dichloromethane-methanol (90:10) and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel (eluent: dichloromethane / methanol 90:10). The product was dissolved in a 1: 1 mixture of ethyl acetate and water, and the solid obtained was filtered and dried to 4.61 g of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridin-2-yl) phenol a28 was obtained as a white solid.

Yield 26%.

Tert-Butyl 2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4H) -carboxylate a29 in the same manner can do.

LC-MS (MH ⁺ ): 333.

1.5 5-acetyl-2- {4-[(trans-3-morpholin-4-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] Pyridine 8 Synthesis.

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) in anhydrous N, N-dimethylacetamide (6 ml) A solution of phenol a28 (0.404 g, 1.47 mmol, 1 eq) was treated with sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol, 1.1 eq) under argon atmosphere. After 30 minutes, cis-3-morpholin-4- ylcyclobutyl 4-methylbenzenesulfonate a18 (0.51 g, 1.64 mmol, 1 eq) was added and the mixture was stirred at 70 ° C. overnight. The mixture was poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / methanol 90:10) to give 0.175 g of 5-acetyl-2- {4-[(trans-3-morpholin-4-ylcyclobutyl) Oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 8 was obtained as a yellow solid.

Yield 29%.

LC-MS (MH ⁺ ): 414.

Compounds 4, 12, 13, 14, 19, 20 and 22 can be synthesized in the same manner.

Example  2. 5-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7-te Trahid Synthesis of ro [1,3] thiazolo [5,4-c] pyridine 4.

2.1 tert-butyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c ] Synthesis of pyridine-5 (4H) -carboxylate 3 .

Sodium hydride 60% (89 mg, 2.22 mmol, 2 eq) was tert-butyl 2- (4-hydroxyphenyl) -6,7-di in anhydrous N, N-dimethylformamide (15 ml) at 0 ° C. To a solution of hydro [1,3] thiazolo [5,4-c] pyridine-5 (4H) -carboxylate a29 (370 mg, 1.1 1 mmol, 1 eq) was added. The mixture was stirred at rt for 30 min, then cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (344 mg, 1.1 1 mmol, 1 eq) was added and the mixture was allowed to 80 ° C. Heated at. After 3 days, sodium hydride (135 mg, 3.33 mmol, 3 eq) and cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (525 mg, 1.66 mmol, 1.5 eq) were added and The mixture was heated at 80 ° C. for 4 more days. The mixture was then concentrated to dryness. The residue was dissolved in ethyl acetate and washed with saturated sodium hydrogen carbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo to afford 618 mg of a crude solid, which was purified by chromatography on silica gel (eluent: ethyl acetate 100%). 335 mg tert-butyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridine-5 (4H) -carboxylate 3 was obtained as an orange solid.

Yield 64%.

LC-MS (MH ⁺ ): 470.

2.2 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c ] Synthesis of Pyridine 5 .

Trifluoroacetic acid (1.5 ml) was added tert-butyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7- in dichloromethane (8 ml). To a solution of dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4H) -carboxylate 3 (280 mg, 0.59 mmol, 1 eq), add the mixture at room temperature for 2 hours. Stirred. The mixture was concentrated to dryness. The residue was dissolved in water and brought to pH 9 with saturated potassium carbonate solution and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 180 mg of 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7- Tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 was obtained as an orange solid.

Yield 83%.

LC-MS (MH ⁺ ): 370.

2.3 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine 4 synthesis.

Triethylamine (91 μl, 0.65 mmol, 1.52 eq) and acetyl chloride (41 mg, 0.52 mmol, 1.2 eq) were added 2- {4-[(trans-3-piperi) in dichloromethane (10 ml) at 0 ° C. Of din-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (160 mg, 0.43 mmol, 1 eq) To the solution. The mixture was stirred at 20 ° C. for 3 hours. Dichloromethane was added and the organic layer was washed successively with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to yield 176 mg of a yellow solid. The crude mixture was purified by chromatography on silica gel (dichloromethane / methanol / ammonia 96: 4: 0.4) to give 95 mg of 5-acetyl-2- {4-[(trans-3-piperidin-1-yl Cyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 4 was obtained as a white solid.

Yield 54%.

LC-MS (MH ⁺ ): 412.

Example  3. 2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7-D Heathrow [1 , 3] thiazolo [5,4-c] pyridine-5 (4H)- Carboxamide  Synthesis of 10.

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo in dichloromethane (32 ml) A solution of [5,4-c] pyridine 5 (1.0 g, 2.7 mmol, 1 eq) was treated with trimethylsilylisocyanate (400 μl, 2.9 mmol, 1.1 eq). The mixture was stirred at rt overnight, quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel (dichloromethane / methanol / ammonia 96: 4: 1) to 410 mg of 2- {4-[(trans-3-py). Ferridin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4H) -carboxamide 10 as a white solid It was.

Yield 36%.

LC-MS (MH < + >): 413.

N-ethyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridine-5 (4H) -carboxamide 21 can be synthesized in the same manner.

Example  4. 5- (morpholine-4- Ilcarbonyl ) -2- {4-[(trans-3-piperidine-1- Ylcyclo Butyl) Oxy ] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 6.

Triphosgen (0.064 g, 0.225 mmol, 0.37 eq) was added 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4 in dichloromethane (10 ml) at 0 ° C. To a solution of 5,6,7-tetrahydro [1.3] thiazolo [5,4-c] pyridine 5 (0.225 g, 0.61 mmol, 1 eq). The mixture was stirred at rt for 1 h, cooled to 0 ° C. and then morpholine (0.053 ml, 0.61 mmol, 1 eq) and triethylamine (0.085 ml, 0.61 mmol, 1 eq) were added. The mixture was stirred at rt overnight and washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / ethanol / ammonia 95: 5: 0.5) to give 0.135 g of 5- (morpholin-4-ylcarbonyl) -2- {4-[(trans-3 -Piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 6 was obtained as a yellow solid.

Yield: 46%.

LC-MS (MH ⁺ ): 483.

Example  5. 5- (morpholine-4- Ilsulfonyl ) -2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 7.

5.1 Synthesis of 4- (1H-imidazol-1-ylsulfonyl) morpholine a31 .

Morpholine (0.35 g, 3.92 mmol, 1 eq) was added to 1- (1H-imidazol-1-ylsulfonyl) -3-methyl-1H-imidazol-3-ium trifluoromethane in acetonitrile (70 ml). To a solution of sulfonate a30 (1.7 g, 4.7 mmol, 1.2 eq) (prepared as described in J. Org. Chem. 2003, 68, 1 15-199)), the mixture was stirred at room temperature overnight I was. The solvent was removed under reduced pressure to give a residue, which was then diluted with ethyl acetate and washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / methanol 99: 1) to afford 0.49 g of 4- (1H-imidazol-1-ylsulfonyl) morpholine a31 .

Yield 48%.

LC-MS (MH ⁺ ): 218.

5.2 Synthesis of 3-methyl-1- (morpholin-4-ylsulfonyl) -1H-imidazol-3-ium trifluoromethanesulfonate a32 .

Methyl trifluoromethanesulfonate (0.25 ml, 2.2 mmol, 1 eq) was added 4- (1H-imidazol-1-ylsulfonyl) morpholine a31 (0.48 g) in dichloromethane (15 ml) at 0 ° C. under argon atmosphere. , 2.2 mmol, 1 eq) was added dropwise to the stirred solution. The mixture was stirred at 0 ° C. for 2 hours, the resulting suspension was filtered and washed with dichloromethane to give 0.6 g of 3-methyl-1- (morpholin-4-ylsulfonyl) -1H-imidazole-3-ium tri Fluoromethanesulfonate a32 was obtained as a white solid which was used directly in the next step without further purification.

Yield: 73%.

LC-MS (MH ⁺ ): 382.

5.3 5- (morpholin-4-ylsulfonyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [ Synthesis of 1,3] thiazolo [5,4-c] pyridine 7 .

3-methyl-1- (morpholin-4-ylsulfonyl) -1H-imidazol-3-ium trifluoromethanesulfonate a32 (0.595 g, 1.56 mmol, 1.2 eq) was added 2 in acetonitrile (20 ml). -{4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (0.48 g, 1.3 mmol, 1 eq) was added and the mixture was stirred at rt overnight. The solvent was removed under reduced pressure to give a residue which was then diluted with ethyl acetate and washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol 97: 3) to give 0.16 g of 5- (morpholin-4-ylsulfonyl) -2- {4-[(trans-3-pi Ferridin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 7 was obtained as a yellow solid.

Yield: 24%.

LC-MS (MH ⁺ ): 519.

Example  6. 2-oxo-2- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7-D Heathrow [1 Synthesis of, 3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanol 11

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo in dichloromethane (18 ml) A solution of [5,4-c] pyridine 5 (1.2 g, 3.2 mmol, 1 eq) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.2 g, 11.4 mmol, 3.5 eq) , 1-hydroxybenzotriazole (0.9 g, 6.5 mmol, 2.0 eq) and N, N-dimethylaminopyridine (0.4 g, 3.2 mmol, 1.0 eq). The mixture was stirred at rt for 30 min and glycolic acid (300 mg, 3.9 mmol, 1.2 eq) was added. The resulting mixture was stirred at rt overnight, quenched with 0.5 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (dichloromethane / methanol / ammonia 96: 4: 0.4) to give 415 mg of 2-oxo-2- [2- {4-[(trans-3-piperidine-1 -Ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanol 11 was obtained as a yellow solid.

Yield: 30%.

LC-MS (MH ⁺ ): 428.

Compounds 41, 42, 53, 60, 63 and 65 can be synthesized in the same manner.

Example  7. 2-oxo-2- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) jade city] Phenyl } -6,7- Dihydro [1,3] tea Azolo [5,4-c] pyridin-5 (4H) -yl] Ethanamine  Synthesis of 9.

7.1 tert-butyl {2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] Synthesis of thiazolo [5,4-c] pyridin-5 (4H) -yl] ethyl} carbamate a33 .

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo in dichloromethane (8 ml) A solution of [5,4-c] pyridine 5 (500 mg, 1.4 mmol, 1.0 eq) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.9 g, 4.9 mmol, 3.5 eq) , 1-hydroxybenzotriazole (380 mg, 2.8 mmol, 2.0 eq) and 4- (N, N-dimethylamino) -pyridine (175 mg, 1.4 mmol, 1.0 eq). The mixture was stirred at 0 ° C. for 10 minutes and N- (tert-butoxycarbonyl) glycine (270 mg, 1.5 mmol, 1.1 eq) was added. The resulting mixture was stirred at rt overnight, then quenched with 0.5 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness tert-butyl {2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) ) Oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethyl} carbamate a33 , which is further purified It was used in the next step without.

LC-MS (MH ⁺ ): 527.

7.2 2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, Synthesis of 4-c] pyridin-5 (4H) -yl] ethanamine 9 .

Trifluoroacetic acid (3.0 ml, 4.5 mmol, 30 eq) was tert-butyl {2-oxo-2- [2- {4-[(trans-3-piperi) in dichloromethane (18 ml) at 0 ° C. Din-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethyl} carbamate a33 (7.4 g, 1.4 mmol, 1.0 eq), and the mixture was stirred at rt overnight. The reaction mixture was treated with saturated aqueous potassium carbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel (dichloromethane / methanol / ammonia 94: 6) to give 59 mg of 2-oxo-2- [2- {4-[(trans-3-piperidin-1-yl Cyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanamine 9 was obtained as a yellow solid.

Yield 10%.

LC-MS (MH ⁺ ): 427.

Example  8. 5- ( Methoxyacetyl ) -2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) jade city] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 2.

Methoxyacetyl chloride (0.066 ml, 0.61 mmol, 1 eq) was added 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} in dichloromethane (10 ml) at 0 ° C. -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (0.225 g, 0.61 mmol, 1 eq) and triethylamine (0.085 ml, 0.61 mmol, 1 eq ) Solution. The mixture was stirred at rt overnight and then washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / methanol 97: 3) to give 0.152 g of 5- (methoxyacetyl) -2- {4-[(trans-3-piperidin-1-ylcyclo Butyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 2 was obtained as a white solid.

Yield 56%.

LC-MS (MH ⁺ ): 442.

Example  9. 3-oxo-3- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7- Dihydro [1,3] tea Azolo [5,4-c] pyridin-5 (4H) -yl] Propanamide  Synthesis of 25.

9.1 Methyl 3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5 , 4-c] pyridin-5 (4H) -yl] propanoate a34 .

Methyl-3-chloro-3-oxopropionate (0.44 g, 3.2 mmol, 1.2 eq) was added to 2- {4-[(trans-3-piperidin-1-ylcyclobutyl in dichloromethane (30 ml). ) Oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (1 g, 2.7 mmol, 1 eq) and triethylamine (0.75 ml, 5.4 mmol, 2 eq). The mixture was stirred at rt overnight and successively washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to yield 1.26 g of methyl 3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6 , 7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propanoate a34 was obtained and used directly in the next step without any other purification.

Yield:> 95%.

LC-MS (MH ⁺ ): 470.

9.2 3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, Synthesis of 4-c] pyridin-5 (4H) -yl] propanamide 25 .

A 7 N ammonia solution in methanol (25 ml) was dissolved in methyl 3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} in methanol (20 ml). To a solution of -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propanoate a34 (1.1 g, 2.34 mmol, 1 eq), The mixture was stirred for 48 h at 70 ° C. in a sealed vessel. The solvent was removed under reduced pressure to give a residue, which was then diluted with dichloromethane and washed twice with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / methanol / ammonia 98: 2: 0.2) to give 0.189 g of 3-oxo-3- [2- {4-[(trans-3-piperidine-1 -Ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propanamide 25 was obtained as a beige solid.

Yield 18%.

LC-MS (MH ⁺ ): 455.

Example  10. methyl  [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl} -6,7- Dihydro [1,3] tea Synthesis of Azolo [5,4-c] pyridin-5 (4H) -yl] acetate 26.

Methyl bromoacetate (460 μl, 4.9 mmol, 1.2 eq) was added to 2- {4-[(trans-3-piperidine-1- in dimethylformamide / acetonitrile (2: 1 v / v, 60 ml). Monocyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (1.5 g, 4.1 mmol, 1.0 eq), potassium phosphate (2.7 g, 12.7 mmol, 2.6 eq) and sodium iodide (189 mg, 1.3 mmol, 0.3 eq). The mixture was stirred at 40 ° C. for 1 hour before water was added. The reaction mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 96: 4) to give 540 mg of methyl [2- {4-[(trans-3-piperidin-1-ylcyclobutyl). ) Oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] acetate 26 was obtained as a yellow solid.

Yield: 30%.

LC-MS (MH ⁺ ): 442.

Example  11. (2S) -3- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7-D Heathrow [1 , 3] Synthesis of thiazolo [5,4-c] pyridin-5 (4H) -yl] propane-1,2-diol 16.

(2R) -3-chloropropane-1,2-diol (0.28 g, 2.53 mmol, 1.2 eq) was added 2- {4-[(trans-3-py) in acetonitrile (35 ml) with catalytic amount of sodium iodide. Ferridin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (0.78 g, 2.11 mmol, 1 eq) And a suspension of potassium carbonate (0.58 g, 4.22 mmol, 2 eq). The mixture was stirred at reflux for 54 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. This organic layer was washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 100: 0: 0 to 95: 5: 0.5) to give 0.197 g of (2S) -3- [2- {4-[(trans -3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propane-1 , 2-diol 16 was obtained as a beige solid.

Yield 21%.

LC-MS (MH ⁺ ): 444.

Chiral chromatography (chiralcel OD-H, iso-hexane / n-propanol / diethylamine 50: 50: 0.1): t _R = 5'49 (ee: 94.8%).

Compounds 15 and 17 can be synthesized in the same manner using 3-chloropropane-1,2-diol and (2S) -3-chloropropane-1,2-diol as reactants, respectively.

Chiral chromatography for compound 17 (chiralcel OD-H, iso-hexane / n-propanol / diethylamine 50: 50: 0.1): t _R = 4'85 (ee: 94%).

Compound 18 can be synthesized using 2-bromoacetamide. Compound 37 can be synthesized using 2-bromoethanol.

Example  12. Sheath -3- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7-D Heathrow [1 , 3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Cyclobutanol  Synthesis of 24.

12.1 3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Synthesis of pyridin-5 (4H) -yl] cyclobut-2-en-1-one a35 .

Trifluoroacetic acid (0.22 ml, 2.97 mmol, 1.1 eq) was added N-cyclohexylcyclohexaneaminium 3-oxocyclobut-1-ene-1-oleate a1 (0.71 g, in dioxane (40 ml). 2.7 mmol, 1 eq) and 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (1.0 g, 2.7 mmol, 1 eq) was added to the stirred suspension. The reaction mixture was stirred at 20 ° C. overnight. The solvent is then removed under reduced pressure, the residue is dissolved with ethyl acetate and the organic layer is washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 1.25 g of 3- [2- { 4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4H)- Il] cyclobut-2-en-1-one a35 was obtained and used directly in the next step without any further purification.

Yield:> 95%.

LC-MS (MH ⁺ ): 436.

12.2 cis-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4- c] Synthesis of pyridin-5 (4H) -yl] cyclobutanol 24 .

3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5 in ethanol (35 ml) , 4-c] pyridin-5 (4H) -yl] cyclobut-2-en-1-one a35 (1.2 g, 2.75 mmol, 1 eq) was dissolved in sodium borohydride (0.52 g, 13.77 mmol, 3.5 eq) parts. At the end of the addition, the mixture was stirred at 70 ° C. overnight. The solvent was removed under reduced pressure, then the residue was diluted with dichloromethane. This organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / heptane / methanol / ammonia 48.5: 48.5: 3: 0.3) to give 0.271 g of cis-3- [2- {4-[(trans-3-piperidine -1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] cyclobutanol 24 as a beige solid It was.

Yield 22%.

LC-MS (MH ⁺ ): 440.

Example  13. 4-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7-te Trahid Synthesis of Rho [1,3] thiazolo [4,5-b] pyridine 30.

13.1 Synthesis of 3- bromopiperidine -2,6-dione a37

Bromine (4.5 ml, 87.8 mmol) is added to a suspension of piperidine-2,6-dione a36 (10.2 g, 50.3 mmol) suspended in chloroform (20 ml) and the mixture is 110 for 90 minutes in a closed container. Stirred at bath temperature of < RTI ID = 0.0 > After cooling, the vessel was opened and stirring continued until no more hydrogen bromide was released. The reaction was evaporated under vacuum. The residue was dissolved in ethanol and evaporated to give 17.1 g of 3- bromopiperidine -2,6-dione a37 as white crystals.

Yield: 99%.

LC-MS (MH ⁺ ): 193.

13.2 Synthesis of 2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [4,5-b] pyridin-5 (4H) -one a39 .

4-hydroxythiobenzamide a38 (50.0 g, 0.33 mmol, 1 eq) and 3- bromopiperidine -2,6-dione a37 in 2-propanol (500 ml) (69.0 g, 0.36 mmol, 1.1 eq) was heated at reflux for 2 hours. The solid was dissolved at about 20 ° C. before the product began to precipitate. The resulting yellow suspension was cooled to 20 ° C., filtered slowly and washed with fresh 2-propanol (2 × 100 ml). The crude product (70.5 g) was dissolved at 70 ° C. using 2: 1 ethanol / water (3.7 L). Remaining undissolved impurities were removed by filtration. The filtrate was heated at reflux for 30 minutes and then the clear solution was slowly drifted to room temperature overnight with stirring. Coarse crystals were collected, which were reslurried in ethanol (200 ml) for 1 hour and then separated again and dried at 50-80 ° C. in vacuo to 38.7 g of 2- (4-hydroxyphenyl) -6,7- Dihydro [1,3] thiazolo [4,5-b] pyridin-5 (4H) -one a39 was obtained as a pale yellow green powder.

Yield 48%.

13.3 Synthesis of 2- (4-hydroxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridine a40 .

2- (4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [4,5-b] pyridin-5 (4H) -one a39 (23.9 g in tetrahydrofuran (500 ml) , 97 mmol) was cooled to 0-5 ° C under nitrogen. Borane-dimethyl sulfide complex (22.8 g, 28.5 ml, 300 mmol) was added dropwise at 4-6 ° C. over about 30 minutes, then washed with tetrahydrofuran (2 × 50 mL). Gas release and mild exotherm were identified at an early stage of this stage. After stirring at 5 ° C. for an additional hour, the preparation was warmed to 20-25 ° C. overnight. The reaction was then quenched by careful addition of methanol (250 ml) (NB exotherm & gas evolution) below 10 < 0 > C. The resulting solution was concentrated by distillation at atmospheric pressure (740 ml solvent removed). Methanol (500 ml) was charged and this operation resumed until an additional 260 ml distillate was collected. The remaining cloudy solution was slowly cooled to 0-5 ° C., the pale yellow crystals formed were filtered off, washed with methanol (2 × 20 ml) and concentrated at 50 ° C. under vacuum to give 9.1 g of 2- (4- Hydroxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridine a40 was obtained as a yellow powder.

Yield 40%.

13.4 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b ] Synthesis of pyridine a41 .

2- (4-hydroxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridine a40 (in anhydrous N, N-dimethylacetamide (90 ml) A solution of 3 g, 12.9 mmol, 1 eq) was treated with sodium hydride (60% dispersion in mineral oil, 0.77 g, 19.35 mmol, 1.5 eq) under argon atmosphere. After 15 minutes, cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (3.19 g, 10.32 mmol, 0.8 eq) was added and the mixture was stirred at 70 ° C. for 60 hours. The mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed twice with water. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient: dichloromethane / ethanol 100: 0 to 80:20) to give 1.24 g of 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) Oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridine a41 was obtained.

Yield 32%.

LC-MS (MH ⁺ ): 370

13.5 4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4 , 5-b] pyridine 30 synthesis.

Acetyl chloride (0.049 ml, 0.62 mmol, 1.2 eq) was added 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5 in dichloromethane (10 ml), To a suspension of 6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridine a41 (0.19 g, 0.51 mmol, 1 eq) and triethylamine (0.086 ml, 0.62 mmol, 1.2 eq) It was. The mixture was stirred at rt overnight and then washed twice with saturated aqueous chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia 95: 5: 0.5) to give 0.03 g of 4-acetyl-2- {4-[(trans-3-piperidine- 1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-b] pyridine 30 was obtained as a beige solid.

Yield: 15%.

LC-MS (MH ⁺ ): 412.

2- (benzyloxy) -1- [2- (4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} phenyl) -6,7-dihydro [1,3] thia Zolo [4,5-b] pyridin-4 (5H) -yl] ethanone a77 can be synthesized according to the same method (LC-MS (MH ⁺ ): 518).

Example  14. 5-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Thio ] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 23.

14.1 Synthesis of 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzoic acid a42 .

Sodium hydride (60% in oil, 520 mg, 12.9 mmol, 1.0 eq) was added to a solution of 4-mercaptobenzoic acid (3.0 g, 12.9 mmol, 1.0 eq) in dimethylformamide (20 ml) at 0 ° C. After 15 minutes, a solution of cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (4.0 g, 12.9 mmol, 1.0 eq) in dimethylformamide (30 ml) was added. The reaction mixture was stirred at 40 ° C. for 6 days. Methanol was added at room temperature. The mixture was concentrated under reduced pressure. The resulting orange solid is removed by filtration, rinsed with ethanol and then recrystallized from a mixture of ethanol / water to give 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzoic acid a42 and by-product as the main product. To give 638 mg of a mixture of disulfide derivatives of 4-mercaptobenzoic acid ( ¹ H NMR ratio: 5: 1). This mixture was used directly in the next step without any further purification.

14.2 Synthesis of 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzamide a43 .

Ammonium bicarbonate (450 mg, 5.7 mmol, 2.6 eq) in 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzoic acid a42 (638 mg, 2.2 mmol in dimethylformamide (6.4 ml) , 1.0 eq), di-tert-butyl bicarbonate (1.2 g, 5.7 mmol, 2.6 eq) and pyridine (230 μl, 2.8 mmol, 1.3 eq). The reaction mixture was stirred at rt overnight, then a solution of 10% n-propanol in ethyl acetate (20 ml) was added. This mixture was washed twice with water. The organic layer was dried over magnesium sulfate and concentrated to dryness to disulfide 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzamide a43 as a main product and 4-mercaptobenzamide as a by-product. 680 mg of a mixture of derivatives were obtained (LC-MS ratio: 4: 1). This mixture was used directly in the next step.

LC-MS (MH ⁺ ): 442.

14.3 Synthesis of 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzenecarbothioamide a44 .

2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphate (Lawessons's reagent (2.6 g, 6.5 mmol, 1.5 eq) To a mixture of 4-[(trans-3-piperidin-1- ylcyclobutyl ) sulfanyl] benzene a43 (1.2 g, 4.3 mmol, 1.0 eq) in tetrahydrofuran (24 ml) was added. Was stirred at room temperature for 3 hours, then the yellow solid was filtered and rinsed with tetrahydrofuran The filtrate was concentrated to dryness to afford crude 4-[(trans-3-piperidin-1-ylcyclobutyl) sulfanyl] Benzenecarbothioamide a44 was obtained and used directly in the next step.

LC-MS (MH < + >): 307.

14.4 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) thio] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine 23 synthesis.

A solution of 1-acetyl-3- bromopiperidin -4-one a27 (1.0 g, 4.5 mmol, 1.1 eq) in isopropanol (25 ml) was added to 4-[(trans-3-piperidin-1-ylcyclo Butyl) sulfanyl] benzenecarbothioamide a44 (1.2 g, 4.0 mmol, 1 eq) and the mixture was stirred at 60 ° C. for 5 days, then 1-acetyl-3-bromo-piperidin-4-one hydrobromide salt (2.0 g , 4.0 mmol, 1.0 eq) was added. The mixture was stirred at 60 ° C. overnight and then cooled to room temperature. Ethyl acetate was added and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel (dichloromethane / methanol / ammonia 96: 4: 1). The product was triturated with ethanol and the solid obtained was filtered and dried to give 100 mg of 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) thio] phenyl} -4,5 , 6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 23 was obtained as a beige solid.

Yield (for 4 steps): 6%.

LC-MS (MH ⁺ ): 428.

Example  15. 4-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -5,6,7,8-te The Lahydro-4H- [1,3] thiazolo [5,4-b] Azepine  Synthesis of 31.

15.1 Synthesis of 4- (benzyloxy) -N- (2- oxoasepan- 3-yl) benzamide a46

At 0 ° C. a suspension of 4- (benzyloxy) benzoic acid a45 (5.0 g, 21.93 mmol, 1 eq) and N, N-dimethylformamide (0.5 ml) in dichloromethane (300 ml) was charged with oxalyl chloride (2.83 ml, 26.32 mmol, 1.2 eq). The mixture was allowed to warm to room temperature and stirred until gas evolution ceased. Half of the solvent was removed under reduced pressure and the resulting solution was washed with DL-a-amino-ε-caprolactam (3.37 g, 26.32 mmol, 1.2 eq) and triethylamine (6.11 ml, 43.86 mmol, in dichloromethane (300 ml). 2 eq) to the mixture. Stir at 20 ° C. for 1 h, then add water (200 ml) and dry the organic layer over magnesium sulfate and concentrate. The residue was dissolved in ethyl acetate, the resulting suspension was filtered and the solid was dried at 40 ° C. under reduced pressure to give 5.9 g of 4-benzyloxy-N- (2- oxoazpan- 3-yl) benzamide a46 . Obtained.

Yield 80%.

LC-MS (MH ⁺ ): 339.

15.2 Synthesis of 2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine hydrochloride a47 .

A suspension of 4-benzyloxy-N- (2- oxoazpan- 3-yl) benzamide a46 (2.0 g, 5.91 mmol, 1 eq) in pyridine (20 ml) was added to a Lawson reagent (1.43 g, 3.55 mmol, 0.6 eq) and the mixture was stirred at 100 ° C. for 20 hours. After cooling to room temperature, the mixture was poured onto saturated aqueous sodium hydrogen carbonate solution (150 ml) and the aqueous layer was extracted with dichloromethane (2 × 100 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in a 1: 1 mixture of ethyl acetate and dichloromethane (50 ml) and the acyclic thioamide was removed by filtration. The organic layer was concentrated and the residue was purified by chromatography on silica gel (heptane / ethyl acetate 3: 1). The main fraction from chromatography was concentrated under reduced pressure. The residue was dissolved in a 1: 5 mixture of methanol / diethyl ether (10 ml) and treated with a 2M solution of hydrogen chloride in diethyl ether (2 ml). The solid obtained was dried at 40 ° C. under vacuum to yield 900 mg of 2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4- b] azepine hydrochloride a47 was obtained.

Yield 23%.

LC-MS (MH ⁺ ): 337.

15.3 Synthesis of 4-acetyl-2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine a48 .

2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine hydrochloride in dichloromethane (40 ml) A suspension of a47 (0.9 g, 2.68 mmol, 1 eq) was added to a solution of triethylamine (1.12 ml, 8.04 mmol, 3 eq), and acetyl chloride (0.23 ml, 3.21 mmol, 1.2 eq) in dichloromethane (5 ml). Treated with. After stirring at 20 ° C. for 2 hours, water (20 ml) is added. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / methanol / ammonia 95: 5: 0.5) to 210 mg of 4-acetyl-2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H -[1,3] thiazolo [5,4-b] azepine a48 was obtained.

Yield 64%.

LC-MS (MH ⁺ ): 379.

15.4 Synthesis of 4- (4-acetyl-5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azin -2-yl) phenol a49 .

4-acetyl-2- [4- (benzyloxy) phenyl] -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] in dichloromethane (10 ml) A solution of azepine a48 (0.6 g, 1.5 mmol, 1 eq) was treated with a solution of boron tribromide 1 M in dichloromethane (8 ml, 8.0 mmol, 5 eq). The mixture was left to stir overnight at 20 ° C. and then water (10 ml) was added. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / methanol / ammonia 95: 5: 0.5) gave 360 mg of 4-(4-acetyl-5,6,7,8-tetrahydro-4H- [1,3] thiazolo [ 5,4-b] azin -2-yl) phenol a49 was obtained.

Yield 79%.

LC-MS (MH ⁺ ): 289.

15.5 4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6,7,8-tetrahydro-4H- [1,3] thia Synthesis of zolo [5,4-b] azepine 31 .

4- (4-acetyl-5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine- in anhydrous N, N-dimethylacetamide (7 ml) A solution of 2-yl) phenol a49 (0.16 g, 0.55 mmol, 1 eq) was treated with sodium hydride (60% dispersion in mineral oil, 0.03 g, 0.83 mmol, 1.5 eq) (under argon atmosphere). After 15 minutes, cis-3-piperidin-1 -ylcyclobutyl 4-methylbenzenesulfonate a25 (0.19 g, 0.61 mmol, 1.1 eq) was added and the mixture was stirred at 60 ° C. for 60 hours. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 ml) and washed with brine (10 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / methanol / ammonia 98: 2: 0.2). The solid obtained after evaporation of the solvent was dried under vacuum at 50 ° C. overnight to give 67 mg of 4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5 , 6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine 31 was obtained as a brown solid.

Yield 36%.

LC-MS (MH ⁺ ): 426.

Example  16. 5-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) jade city] Phenyl } -4,5,6,7- Tetrahydro [1,3] oxazolo Synthesis of [4,5-c] pyridine 28.

16.1 Synthesis of 4- (benzyloxy) -N- (4-hydroxypyridin-3-yl) benzamide a50 .

At 0 ° C. a suspension of 4- (benzyloxy) benzoic acid a4 5 (10.0 g, 43.81 mmol, 1 eq) and N, N-dimethylformamide (0.5 ml) in dichloromethane was charged with oxalyl chloride (5.18 ml, 48.19 mmol, 1.1 eq). This mixture was allowed to warm to room temperature. When gas evolution ceased, half of the solvent was removed under reduced pressure, and the solution was washed with 3-aminopyridin-4-ol (4.82 g, 43.81 mmol, 1 eq) and triethylamine (12.15 ml, in dichloromethane (300 ml). 87.62 mmol, 2 eq) was added dropwise. The mixture was stirred at 20 ° C. for 24 h and water (200 ml) was added. The aqueous phase was extracted with a 9: 1 mixture of dichloromethane and methanol (2 x 300 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate (50 ml) and the resulting suspension was filtered off. The solid was dried at 40 ° C. under vacuum to afford 10 g of 4- (benzyloxy) -N- (4-hydroxypyridin-3-yl) benzamide a50 .

Yield 71%.

LC-MS (MH ⁺ ): 321.

16.2 Synthesis of 2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine a51 .

A solution of hexachloroethane (16.81 g, 71.02 mmol, 2.5 eq) in anhydrous dichloromethane (300 ml) was purified by triphenylphosphine (22.35 g, 85.22 mmol, 3 eq) and triethylamine (31.68 ml, 227.25 mmol, 8 eq). After stirring for 10 min at 20 ° C., 4- (benzyloxy) -N- (4-hydroxypyridin-3-yl) benzamide a50 (9.1 g, 28.41 mmol, 1 eq) was added in several portions. The suspension was stirred at 20 ° C. overnight and filtered. This solid was triturated with a 1 M aqueous hydrogen chloride solution and the suspension was removed by filtration. The solid was rinsed with diethyl ether and dried at 40 ° C. in vacuo to give 7.9 g of 2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine a51 .

Yield 92%.

LC-MS (MH ⁺ ): 303.

16.3 Synthesis of 5-benzyl-2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine-5-ium a52 .

Of 2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine a51 (2.0 g, 6.62 mmol, 1 eq) in N, N-dimethylformamide (10 ml) The solution was treated with benzyl bromide (0.9 ml, 7.28 mmol, 1.1 eq) and stirred at 20 ° C. for 1 hour and then at 60 ° C. overnight. After cooling to 20 ° C., ethyl acetate (50 ml) was added to the mixture. The resulting suspension is removed by filtration and the solid is dried at 40 ° C. in vacuo to give 2.6 g of 5-benzyl-2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] Pyridine-5-ium a52 was obtained.

Yield: 100%.

LC-MS (MH ⁺ ): 393.

16.4 Synthesis of 5-benzyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine a53 .

5-benzyl-2- [4- (benzyloxy) phenyl] [1,3] oxazolo [4,5-c] pyridine-5-ium a52 (2.6 g, 6.61 mmol, 1 eq in ethanol (150 ml) ) Solution was treated with sodium borohydride (1.0 g, 26.43 mmol, 4 eq) portions and the mixture was stirred at 60 ° C. for 2 hours and then at 20 ° C. overnight. Water (1 ml) was added and the mixture was concentrated under reduced pressure. This mixture was dissolved in a 1: 1 mixture of dichloromethane and water (40 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / methanol / ammonia 90: 9: 1) gave 0.97 g of 5-benzyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1 , 3] oxazolo [4,5-c] pyridine a53 was obtained.

Yield: 46%.

LC-MS (MH ⁺ ): 397.

16.5 Synthesis of 4- (4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol a54 .

5-benzyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] oxazolo [4, in a 1: 1 mixture of ethyl acetate and acetic acid (10 ml) A solution of 5-c] pyridine a53 (0.97 g, 2.4 mmol, 1 eq) was stirred overnight at 70 ° C. and hydrogen (20 bar) in an autoclave. The mixture was filtered and the filtrate was concentrated to dryness to give 0.5 g of 4- (4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol a54 . Obtained.

Yield: 100%.

LC-MS (MH ⁺ ): 217.

16.6 Synthesis of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenyl acetate a55 .

4- (4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol a54 (0.6 g, 2.77 mmol, 1 in dichloromethane (10 ml) eq) was treated with triethylamine (0.85 ml, 6.1 mmol, 2.2 eq) and acetyl chloride (0.48 g, 6.1 mmol, 2.2 eq). The mixture was stirred overnight and water (10 ml) was added. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel (dichloromethane / methanol / ammonia 97: 3: 0.3) gave 0.3 g of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5 -c] pyridin-2-yl) phenyl acetate a55 was obtained.

Yield 36%.

LC-MS (MH ⁺ ): 301.

16.7 Synthesis of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenol a56 .

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) phenyl acetate a55 (0.3 in tetrahydrofuran (10 ml) g, 1.16 mmol, 1 eq) was treated with a lithium hydroxide solution (50 mg, 1.16 mmol, 1 eq) in water (0.5 ml). After stirring at 70 ° C. for 2 hours, the mixture was concentrated under reduced pressure. This residue was dissolved in water (10 ml) and 1 M aqueous solution of hydrochloric acid (2.0 ml). This aqueous layer was extracted with dichloromethane (2 x 10 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 230 mg of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine-2- I) phenol a56 was obtained.

Yield 85%.

LC-MS (MH ⁺ ): 259.

16.8 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] oxazolo [4 , 5-c] pyridine 28 synthesis.

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl) in anhydrous N, N-dimethylformamide (10 ml) Phenol a56 A solution of (0.2 g, 0.78 mmol, 1 eq) was treated with potassium tert-butoxide (0.27 g, 2.34 mmol, 3 eq) under argon atmosphere. After 15 minutes, cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (0.23 g, 0.78 mmol, 1 eq) was added. The mixture was stirred at 80 ° C. overnight, concentrated under reduced pressure, diluted with ethyl acetate (20 ml) and washed twice with brine (2 × 20 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid 5/95 / 0.1 to 35/65 / 0.1). After concentration under reduced pressure, the residue was dissolved in dichloromethane (20 ml), washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated to dryness to 20 mg of 5-acetyl-2- {4-[( Trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine 28 as a white solid It was.

Yield: 7%.

LC-MS (MH ⁺ ): 396.

Example  17. 5-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [4,5-c] pyridine 29.

17.1 Synthesis of 4- (benzyloxy) benzoyl chloride a57 .

A solution of 4- (benzyloxy) benzoic acid a45 (17.76 g, 77.8 mmol, 1 eq) in dichloromethane (700 ml) and N, N-dimethylformamide (400 μl) was converted to oxalyl chloride (9.2 ml, 85.58 mmol, 1.1 eq). The mixture was stirred at 20 ° C. for 20 hours. The mixture was then concentrated under reduced pressure and used as such in the next step.

17.2 4- (benzyloxy) -N- (4-chloropyridin-3-yl) benzamide synthesis of a58 .

A solution of 3-amino-4-chloropyridine (10 g, 77.8 mmol, 1 eq) in N, N-dimethylformamide (300 ml) was added to sodium hydride (60% dispersion in mineral oil, 6.85 g, 171 mmol, 2.2 eq). After stirring for 1 h at 20 ° C., the resulting solution was treated dropwise with a solution of 4- (benzyloxy) benzoyl chloride a57 (19.193 g, 77.8 mmol, 1 eq) in dichloromethane (300 ml). This mixture was stirred at 20 ° C for 24 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with water followed by brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (700 ml) and treated with a suspension of sodium hydride (60% dispersion in mineral oil, 3.1 g, 124 mmol, 1.6 eq). After stirring at 20 ° C. for 2 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 ml) and sonicated. Solid that precipitated (4- (benzyloxy) benzoic acid) was removed by filtration and the resulting solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 ml) and left overnight. The suspension was filtered again and the solid was washed with ethyl acetate and dried. The filtrate was concentrated and the residue was purified by chromatography on silica gel (dichloromethane / methanol 99: 1). Two batches of solids were pooled together to yield 10.8 g of 4- (benzyloxy) -N- (4-chloropyridin-3-yl) benzamide a58 .

Yield: 41%.

LC-MS (MH ⁺ ): 339/341.

17.3 Synthesis of 2- [4- (benzyloxy) phenyl] [1,3] thiazolo [4,5-c] pyridine a59 .

A solution of 4- (benzyloxy) -N- (4-chloropyridin-3-yl) benzamide a58 (6.9 g, 20.37 mmol, 1 eq) in toluene (200 ml) was added with 2,4-bis (4-meth). Treated with oxyphenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawson reagent, 5.766 g, 14.26 mmol, 0.7 eq) and the mixture was stirred at 110 ° C. for 20 hours. . After cooling to room temperature, water (400 ml) was added. The aqueous layer was extracted with toluene (400 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 ml) and sonicated. The resulting suspension was filtered, washed with ethyl acetate and dried under vacuum to give a solid in the first batch. The filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (dichloromethane / methanol 99: 1) to give a second batch. Two batches of solids were combined to yield 2.54 g of 2- [4- (benzyloxy) phenyl] [1,3] thiazolo [4,5-c] pyridine a59 .

Yield 40%.

LC-MS (MH ⁺ ): 319.

17.4 Synthesis of 2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-pyridine a60 .

2- [4- (benzyloxy) phenyl] [1,3] thiazolo [4,5-c] pyridine a59 (1 g, 3.14 mmol, 1 eq) and platinum (IV) oxide in acetic acid (150 ml) A suspension of 142.6 mg, 0.63 mmol, 0.2 eq) was stirred overnight at 70 ° C. under hydrogen atmosphere (50 bar) in autoclave. The mixture is then filtered over celite and concentrated to dryness to afford 2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine A60 was obtained and used directly in the next step without any further purification.

Yield: 100%

LC-MS (MH ⁺ ): 323.

17.5 Synthesis of 5-acetyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine a61 .

Dichloromethane (60 ml) of 2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridin-a60 (2.028 g, 6.29 mmol, 1 eq), acetic anhydride (96 mg, 9.44 mmol, 1.5 eq) and 4- (N, N-dimethylamino) pyridine (77 mg, 0.63 mmol, 0.1 eq) at 40 ° C. for 1 h 30 min Was stirred. Water was then added, the organic layer was collected, dried over magnesium sulfate and concentrated under reduced pressure. The resulting material was purified by chromatography on silica gel (dichloromethane / methanol 99: 1) to give 450 mg of pure 5-acetyl-2- [4- (benzyloxy) phenyl] -4,5,6,7- Tetrahydro [1,3] thiazolo [4,5-c] pyridine a61 was obtained.

Yield 50%.

LC-MS (MH ⁺ ): 365.

17.6 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridin-2-yl) phenol synthesis of a62 .

5-acetyl-2- [4- (benzyloxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine a61 in dichloromethane (30 ml) 1.1 g, 3.02 mmol, 1 eq) was cooled to 0 ° C. This mixture was treated by dropwise addition of boron tribromide 1M solution in dichloromethane (18 ml, 18.1 1 mmol, 6 eq). The mixture was allowed to warm to rt and stirred for 2 h. Water was added and the mixture was extracted with a 90:10 mixture of dichloromethane / methanol. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure to give 370 mg of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [ 4,5-c] pyridin-2-yl) phenol a62 was obtained, which was used directly in the next step without any further purification.

Yield: 45%

LC-MS (MH ⁺ ): 275.

17.7 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4 , 5-c] pyridine 29 synthesis.

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridin-2-yl) phenol in N, N-dimethylacetamide (10 ml) A solution of a62 (370 mg, 1.02 mmol, 1 eq) was treated with sodium hydride (60% dispersion in mineral oil, 81.2 mg, 2 mmol, 2 eq). This mixture was stirred at rt for 10 min. Cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (527 mg, 1.5 mmol, 1.5 eq) was added and the mixture was heated at 70 ° C. for 3 days. After cooling to rt, brine was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / methanol 95: 5 to 90:10) yields 246 mg of 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl } -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine 29 was obtained as a beige solid.

Yield 67%.

LC-MS (MH ⁺ ): 412.

Example  18. 2- {4-[(3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -5,6- Dihi Draw-4H- Cyclopenta [d] [1,3] thiazole -5- Carboxylic acid  Synthesis of 1.

18.1 Synthesis of Methyl 3-bromo-4-hydroxycyclopentanecarboxylate a64 .

Methyl cyclopenta-3-ene-1-carboxylate a63 in acetonitrile (70 ml) A solution of (6.69 g, 53 mmol, 1 eq) was treated with calcium carbonate (5.3 g, 53 mmol, 1 eq) in water (18 ml). The mixture was cooled to 0 ° C. and a solution of N-bromosuccinimide (9.44 g, 53 mmol, 1 eq) in acetonitrile (70 ml) was added slowly. The mixture was stirred at rt for 4 h, filtered and concentrated in vacuo. Water was then added and the product extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting orange solid was dissolved in dichloromethane. The solid was then filtered off, rinsed with dichloromethane and the filtrate was concentrated in vacuo to afford 10.71 g of methyl 3-bromo-4-hydroxycyclopentanecarboxylate a64 as an orange oil.

Yield: 90%.

GC-MS (M ⁺ .): 222/224.

18.2. Synthesis of Methyl 3-bromo-4-oxocyclopentanecarboxylate a65 .

A solution of methyl 3-bromo-4-hydroxycyclopentanecarboxylate a64 (5.58 g, 25 mmol, 1 eq) in dichloromethane (200 ml) was cooled to 0 ° C. and 1 in dichloromethane (130 ml) Treated with 15% solution of 1,1-triacetoxy-1,1-dihydro-1,2-benzidoxo-3 (1H) -one (des-martin reagent). The mixture was stirred at rt for 48 h. A saturated solution of sodium thiosulfate was added and the mixture was stirred for 1 hour. Water was added, the two layers were separated, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine. It was dried over magnesium sulfate and concentrated under reduced pressure. The resulting brown oil was dissolved in dichloromethane, heated and the solids removed by filtration. The dichloromethane solution was concentrated in vacuo, the residue was dissolved in diethyl ether, sonicated, the solids were removed by filtration and the solution was concentrated under reduced pressure. Methyl 3-bromo-4-oxocyclopentanecarboxylate a65 (4.57 g) was obtained as an orange oil which was used directly in the next step without any further purification.

Yield 83%.

GC-MS (M ⁺ .): 220/222.

18.3. Synthesis of ethyl 2- [4-hydroxyphenyl] -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5-carboxylate a66 .

Methyl 3-bromo-4-oxocyclopentanecarboxylate a65 in ethanol (40 ml) A solution of (4.1 g, 18.5 mmol, 1 eq) was treated with 4-hydroxythiobenzamide a38 (2.8 g, 18.5 mmol, 1 eq). The reaction was stirred at reflux overnight. Then the mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, neutralized with aqueous HCl 1N solution, dried over magnesium sulfate and concentrated in vacuo to 2.7 g of ethyl 2- [4-hydroxyphenyl] -5,6-dihydro- 4H-cyclopenta [d] [1,3] thiazole-5-carboxylate a66 was obtained.

Yield 51%.

LC-MS (MH ⁺ ): 290.

18.4 ethyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole- Synthesis of 5-carboxylate a67 .

Ethyl 2- (4-hydroxyphenyl) -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5- in N, N-dimethylformamide (20 ml) at 0 ° C. To a solution of carboxylate a66 (540 mg, 1.99 mmol, 1 eq) was added 60% sodium hydride (159 mg, 3.98 mmol, 2 eq). The mixture was stirred at rt for 30 min, then cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (615 mg, 1.99 mmol, 1 eq) was added and the mixture was 80 ° C. Heated at. After overnight, sodium hydride (80 mg, 1.99 mmol, 1 eq) and cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (310 mg, 1 mmol, 0.5 eq) were added And the mixture was heated at 80 ° C. overnight. The mixture was then concentrated to dryness. The residue was dissolved in ethyl acetate and washed with saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo to yield 580 mg of red oil. The crude mixture was purified by chromatography on silica gel (dichloromethane followed by dichloromethane / methanol / ammonia 85: 15: 1.5) to give two fractions. The first fraction, orange oil, is ethyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1 , 3] thiazole-5-carboxylate a67 (155 mg, yield: 18%, LC-MS (MH ⁺ ): 427). The second solid, red solid, is crude 2- {4-[(3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1, 3] thiazole-5-carboxylic acid (100 mg, yield: 13%, LC-MS (MH ⁺ ): 399).

18.5 2- {4-[(3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5-carr Synthesis of Acid 1 .

A solution of lithium hydroxide monohydrate (30 mg, 0.70 mmol, 2 eq) in water (1.4 ml) was added to ethyl 2- {4-[(trans-3-piperidine-1- in tetrahydrofuran (7 ml). In a solution of monocyclobutyl ) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5-carboxylate a67 (150 mg, 0.35 mmol, 1 eq) Was added and the mixture was heated at reflux overnight. Water (15 ml) was added and the aqueous phase was washed with ethyl acetate, acidified to pH 6 with 1N aqueous hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 40 mg of crude product. Most of the product was in the aqueous layer. The crude product, the aqueous layer and the second fraction from the previous step were combined and purified by reverse phase chromatography (acetonitrile / water / trifluoroacetic acid 5: 95: 0.1 to 95: 5: 0.1) to give 100 mg of 2- {4-[(3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5-carboxylic acid 1 Was obtained as an orange solid.

Yield 19%.

LC-MS (MH ⁺ ): 399.

Example  19. Diethyl  {[2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7-D Heathrow [1 , 3] thiazolo [5,4-c] pyridin-5 (4H) -yl] methyl } Phosphonates  Synthesis of 27.

Benzotriazole (0.16 g, 1.35 mmol, 1 eq) and 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy in a mixture of methanol (8 ml) and water (0.4 ml) ] Phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (0.5 g, 1.35 mmol, 1 eq) was stirred at 25 ° C. for 20 minutes It was. The mixture was stirred vigorously and formaldehyde (37% aqueous solution, 1.28 ml, 1.49 mmol, 1.1 eq) was added. After 4 hours, the suspension is filtered and the precipitate is washed with cold methanol (2 ml). Zinc dibromide (0.3 g, 1.3 mmol, 1.2 eq) and triethylphosphite (0.22 ml, 1.3 mmol, 1.2 eq) were added successively to the benzotriazolyl intermediate in anhydrous dichloromethane (30 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours, then at 20 ° C. for 20 hours, and the reaction was quenched with water (10 ml). After extraction with dichloromethane, the combined organic layers were washed successively with aqueous sodium hydroxide 1N solution (20 ml) and brine (20 ml) and dried over magnesium sulfate. The solvent was removed under vacuum and the residue was recrystallized to give 0.68 g of {[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] methyl} phosphonate 27 was obtained as a yellow sticky solid.

Yield 96%.

LC-MS (MH ⁺ ): 520.

Example  20. 2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } [1,3] thiazolo [ 4,5-c] pyridine  Synthesis of 32.

20.1 Synthesis of 1- [trans-3- (4- iodophenoxy ) cyclobutyl] piperidine a68 .

A solution of 4-iodophenol (15.4 g, 70.3 mmol, 1.5 eq) in anhydrous N, N-dimethylformamide (65 ml) was added to sodium hydride (60% dispersion in mineral oil, 2.0 g, 84.3 mmol, 1.8 eq). After 30 minutes, cis-3-piperidin-1- ylcyclobutyl 4-methylbenzenesulfonate a25 (14.5 g, 46.9 mmol, 1 eq) was added and the mixture was stirred at 70 ° C. for 2 days. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / ethanol / ammonia 97: 2.7: 0.3 in dichloromethane 100%) to give 1- [trans-3- (4-iodophenoxy) cyclobutyl] piperidine a68 was obtained as an orange solid (1 1.5 g).

Yield 69%.

LC-MS (MH ⁺ ): 358.

20.2 Synthesis of N- (4-chloropyridin-3-yl) -4-[(trans-3-piperidin-1- ylcyclobutyl ) oxy] benzamide a69 .

In a process vessel, 1- [3- (4- iodophenoxy ) -cyclobutyl] -piperidine a68 (2.8 g, 7.8 mmol, 1 eq) and palladium (II) acetate (352 mg, 1.6 mmol, 0.2 eq ), Molybdenum hexacarbonyl (2277 mg, 8.6 mmol, 1.1 eq) and anhydrous tetrahydrofuran (36 ml). This vessel was covered with Teflon stopper under argon and the mixture was cooled to 0 ° C. using an ice bath. 1,8-diazabicyclo [5.4.0] undec-7-ene (2.98 g, 19.6 mmol, 2.5 eq) was added. The vessel was stirred at 125 ° C. for 20 minutes while irradiating with microwave. After cooling, the reaction mixture was filtered through a short pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (dichloromethane / methanol 98: 2) to give 960 mg of pure N- (4-chloropyridin-3-yl) -4-[(trans-3-piperidine-1 -Ylcyclobutyl ) oxy] benzamide a69 was obtained.

Yield 31%.

LC-MS (MH ⁺ ): 386/388.

20.3 Synthesis of 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} [1,3] thiazolo [4,5-c] pyridine 32 .

N- (4-chloropyridin-3-yl) -4-[(trans-3-piperidin-1- ylcyclobutyl ) oxy] benzamide a69 (300 mg, 0.78 mmol, 1 in toluene (10 ml) eq) treated with 2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawson reagent, 220 mg, 0.54 mmol, 0.7 eq) The mixture was stirred at 110 ° C. for 20 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (dichloromethane / methanol 90:10) to give 205 mg of pure 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} [ 1,3] thiazolo [4,5-c] pyridine 32 was obtained.

Yield 72%.

LC-MS (MH ⁺ ): 366.

Example  21. 2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -5- (3,3,3-trifluoropropanoyl) -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 33.

Oxalyl chloride (0.16 ml, 1.49 mmol, 1.1 eq) and N, N-dimethylformamide (0.1 ml) were dissolved in 3,3,3-trifluoropropanoic acid (0.19 g, 1.49 mmol, 1.1 eq) was added to the solution. The reaction mixture was warmed at 25 ° C. and concentrated. The residue was washed with 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3 in dichloromethane (20 ml). ] Thiazolo [5,4-c] pyridine 5 (0.5 g, 1.35 mmol, 1 eq) and triethylamine (0.47 ml, 3.38 mmol, 2.5 eq) were added. The mixture was stirred at 25 ° C. overnight, then washed with aqueous potassium hydrogen sulfate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 98: 2: 0.2 to 90: 10: 1) to give 270 mg of 2- {4-[(trans-3-piperidine- 1-ylcyclobutyl) oxy] phenyl} -5- (3,3,3-trifluoropropanoyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4- c] pyridine 33 was obtained.

Yield: 40%

LC-MS (MH ⁺ ): 480.

Ethyl oxo [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] acetate 49 can be synthesized in the same manner.

Example  22. 5-[(5- methyl -2H-1,2,3- Triazole -4-yl) carbonyl] -2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 35.

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] Pyridine 5 (0.5 g, 1.35 mmol, 1 eq) was added to 5-methyl-2H-1,2,3-triazole-4-carboxylic acid (0.21 g, 1.62 in N, N-dimethylformamide (15 ml). mmol, 1.2 eq) and hydroxybenzotriazole (0.22 g, 1.62 mmol, 1.2 eq). 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.31 g, 1.62 mmol, 1.2 eq) was added to the mixture and stirred at 25 ° C. for 30 minutes. Triethylamine (0.73 ml, 1.62 mmol, 1.2 eq) was then added and the mixture was stirred at 25 ° C. for 20 hours. The solvent was concentrated under reduced pressure and the residue was dissolved in dichloromethane / methanol 90:10, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to yield 0.7 g of crude product. The residue was purified by chromatography on silica gel (gradient: acetonitrile / water / ammonia 5: 95: 0.1 to 60: 40: 0.1) to give 0.35 g of 5-[(5-methyl-2H-1,2 , 3-triazol-4-yl) carbonyl] -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 35 was obtained.

Yield 54%.

LC-MS (MH ⁺ ): 479.

Compounds 43, 44, 45, 46, 47, 52 and 54 can be synthesized in the same manner.

Example  23. 3- Isopropoxy -4- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7- Dihydro [1,3] tea Azolo [5,4-c] pyridin-5 (4H) -yl] Cycloboot -3-ene-1,2-dione 56 and 3-hydroxy-4- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7-D Heathrow [1 , 3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Cycloboot -3-yen-1,2- Dion  Synthesis of 55.

23.1 3-isopropoxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [ 5,4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione 56 .

3,4-Diisopropoxycyclobut-3-ene-1,2-dione (0.72 g, 3.66 mmol, 1.5 eq) was added 2- {4-[(trans-3-piperi) in methanol (10 ml). Of din-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 5 (900 mg, 2.44 mmol, 1 eq) To the solution. The mixture was stirred at rt for 60 h and then concentrated under reduced pressure to afford 2 g of crude product. The residue was purified by chromatography on silica gel (gradient: acetonitrile / water / ammonia 5: 95: 0.1 to 60: 40: 0.1). The resulting oil was triturated in anhydrous ether to give 660 mg of 3-isopropoxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7- Dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione 56 was obtained as a white solid.

Yield 56%.

LC-MS (MH ⁺ ): 508.

3-amino-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione. 1/2 trifluoroacetate 58 can be synthesized in the same manner.

23.2 3-hydroxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5 , 4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione 55 .

HCl 6N (1 ml) was dissolved in 3-isopropoxy-4- [2- {4-[(trans-3-piperidine-) in ethanol (10 ml), methanol (10 ml) and dichloromethane (10 ml). 1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2 -Dion 56 (330 mg, 0.65 mmol, 1 eq) was added to the solution and the mixture was stirred for 4 days. HCl 6N (5 ml) was added and the mixture was stirred for an additional 5 hours. The mixture was filtered over celite and concentrated. The residue was purified by chromatography on silica gel (gradient: acetonitrile / water / ammonia 5: 95: 0.1 to 60: 40: 0.1) to give 300 mg of 3-hydroxy-4- [2- {4-[( Trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] cyclobut 3-en-1,2-dione 55 was obtained as a white solid.

Yield: 100%

LC-MS (MH ⁺ ): 466.

Example  24. {[2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7- D Heathrow [ 1,3] tee Azolo [5,4-c] pyridin-5 (4H) -yl] methyl } Synthesis of phosphonic acid 34.

Bromotrimethylsilane (0.7 ml, 5.3 mmol, 4.45 eq) was converted to diethyl {[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl in acetonitrile (10 ml). } -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] methyl} phosphonate 27 (620 mg, 1.19 mmol, 1 eq) in a solution Added. The mixture was stirred at rt overnight. Water was added to the mixture, then concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (gradient: acetonitrile / water / ammonia 5:95 to 30:70) to give 53 mg of {[2- {4-[(trans-3-piperidine- 1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] methyl} phosphonic acid 34 as yellow powder It was.

Yield 10%.

LC-MS (MH ⁺ ): 464.

Example  25. 2-oxo-2- [2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7- Dihydro [1,3] tea Synthesis of azolo [4,5-b] pyridin-4 (5H) -yl] ethanol 66.

Boron tribromide 1 M solution in dichloromethane (41.7 ml, 41.7 mmol, 6 eq) was added to 2- (benzyloxy) -1- [2- (4-{[trans-3- (blood) in dichloromethane (80 ml). Ferridin-1-yl) cyclobutyl] oxy} phenyl) -6,7-dihydro [1,3] thiazolo [4,5-b] pyridin-4 (5H) -yl] ethanone a77 (3.6 g , 6.95 mmol, 1 eq) was added dropwise. The mixture was stirred at 25 ° C. for 1.5 h and poured onto crushed ice and water. The layers were separated and the organic layer was washed once with water and once with saturated aqueous ammonium chloride solution, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 96: 4: 0.4) to give 165 mg of 2-oxo-2- [2- {4-[(trans-3-pi). Ferridin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5-b] pyridin-4 (5H) -yl] ethanol 66 as a beige solid Obtained.

Yield 5.6%.

LC-MS (MH ⁺ ): 428.

Example  26. 5-acetyl-2- {2- Fluoro -4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy] Phenyl ] -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 36.

26.1 Synthesis of 2-fluoro-4-hydroxybenzenecarbothioamide a79 .

A solution of phosphorus hemipentasulfide (22 g, 49.6 mmol, 2 eq) in ethanol (50 ml) under argon atmosphere was added with 2-fluoro-4-hydroxybenzonitrile a78 (3.4 g, 24.8 mmol, 1 at 25 ° C). eq). The mixture was stirred at 80 ° C. overnight, then diluted with diethyl ether and carefully washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in hexane and the precipitate was filtered off, dissolved in N, N-dimethylformamide and dried to give 4.24 g of 2-fluoro-4-hydroxybenzenecarbothioamide a79 as an orange solid.

Yield: 100%.

LC-MS (MH ⁺ ): 172.

26.2 Synthesis of 3-fluoro-4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol a80 .

3-Bromo-piperidin-4-one hydrobromide (6.42 g, 24.8 mmol, 1 eq) was added 2-fluoro-4-hydroxybenzene in N, N-dimethylformamide (80 ml) under argon atmosphere. To a solution of carbothioamide a79 (4.24 g, 24.8 mmol, 1 eq). The mixture was stirred at 50 ° C. overnight and then concentrated under reduced pressure (m = 6.2 g). 3-fluoro-4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol a80 was purified to the next step without any further purification. Used.

Yield: 100%.

LC-MS (MH ⁺ ): 251.

26.3 Synthesis of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -3-fluorophenyl acetate a81 .

3-fluoro-4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenol a80 in dichloromethane (100 ml) (6.2 g, 24.8 mmol, 1 eq) was treated with acetic anhydride (11.5 ml, 122.23 mmol, 4.92 eq) and 4-dimethylaminopyridine (1 g, 8.18 mmol, 0.33 eq). The mixture was stirred at 40 ° C. for 60 hours, diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 99: 0.9: 0.1 followed by heptane / dichloromethane / methanol / ammonia 49: 49: 1.8: 0.2) to give 1.2 g of 4- ( 5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -3-fluorophenyl acetate a81 was obtained.

Yield 14%.

LC-MS (MH ⁺ ): 335.

26.4 1- [2- (2-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone synthesis of a82 .

Sodium (approx. 100 mg) in 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) in methanol (10 ml) To a solution of -3-fluorophenyl acetate a81 (1.2 g, 3.59 mmol, 1 eq) was added and the mixture was stirred at 25 ° C. for 3 hours. The mixture was concentrated under reduced pressure to yield 1.105 g of crude 1- [2- (2-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] ethanone a82 was obtained as a solid, which was used in the next step without any further purification.

Yield: 100%.

LC-MS (MH ⁺ ): 293.

26.5 5-acetyl-2- {2-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3 ] Synthesis of thiazolo [5,4-c] pyridine 36 .

1- [2- (2-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (in tetrahydrofuran (50 ml) 4H) -yl ] ethanone a82 (1.05 g, 3.59 mmol, 1 eq) was treated with molecular sieve (600 mg), 15-crown-5 (1.28 ml, 7.18 mmol, 2 eq) under argon atmosphere, The mixture was stirred at 30 ° C. for 30 minutes. Sodium hydride (60% in mineral oil, 287 mg, 7.18 mmol, 2 eq) was added and the mixture was stirred at 60 ° C. for 1 hour. Then 4-bromo-benzenesulfonic acid 3-piperidin-1-yl-cyclobutyl ester (1.48 g, 3.95 mmol, 1.1 eq) was added and the mixture was heated at 60 ° C. for 17 days. The mixture was dissolved in water, extracted three times with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on alumina (gradient: dichloromethane / hexanes 60:40 to 100: 0) to give an orange solid. This solid was triturated in diethyl ether to give 270 mg of 5-acetyl-2- {2-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5 , 6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 36 was obtained as a beige solid.

Yield 16%.

LC-MS (MH ⁺ ): 430.

Example  27. 5-acetyl-2- {3- Fluoro -4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy] Phenyl } -4,5,6,7- Tetrahydro [1,3] tea Synthesis of Azolo [5,4-c] pyridine 39.

27.1 Synthesis of 3-fluoro-4-methoxybenzenecarbothioamide a84 .

A solution of 3-fluoro-4-methoxybenzamide a83 (5.09 g, 30.1 mmol, 1 eq) in tetrahydrofuran (220 ml) was added to a Lawson reagent (17.05 g, 42.1 mmol, 1.4 eq) at 0 ° C. under argon. ). The mixture was stirred at 25 ° C. overnight. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the precipitate was filtered to give 4.51 g of 3-fluoro-4-methoxybenzenecarbothioamide a84 as a yellow solid.

Yield 81%.

LC-MS (MH ⁺ ): 186.

The following compounds can be synthesized in the same way:

a85 2,6-difluoro-4-methoxybenzenecarbothioamide LC-MS (MH ⁺ ): 204 a86 2,3-difluoro-4-methoxy-thiobenzamide LC-MS (MH ⁺ ): 204

27.2 Synthesis of 2- (3-fluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [ 5,4- pyridine a87 .

3-Bromo-piperidin-4-one hydrobromide (6.21 g, 24 mmol, 1 eq) was added to 3-fluoro-4-methoxybenzene in N, N-dimethylformamide (80 ml) under argon atmosphere. To a solution of carbothioamide a84 (4.44 g, 24 mmol, 1 eq). The mixture was stirred at 50 ° C. for 7 days, then concentrated under reduced pressure and purified by chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 98: 2: 0.2 to 97: 3: 0.3) to give 2.73 g of 2- (3-fluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine a87 was obtained as a yellow solid.

Yield 43%.

LC-MS (MH ⁺ ): 265.

The following compounds can be synthesized in the same way:

a88 2- (2,6-difluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine LC-MS (MH ⁺ ): 283 a89 2- (2,3-difluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine LC-MS (MH ⁺ ): 283

27.3 1- [2- (3-fluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone synthesis of a90 .

2- (3-fluoro-4-methoxyphenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine a87 (2.7 in dichloromethane (35 ml) g, 10.2 mmol, 1 eq) was treated with acetic anhydride (1.45 ml, 15.3 mmol, 1.5 eq) and 4-dimethylaminopyridine (0.13 g, 1.06 mmol, 0.1 eq). The mixture was stirred at 40 ° C. for 3 hours. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford 3.19 g of 1- [2- (3-fluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl ] ethanone a90 was obtained as a beige solid.

Yield: 100%.

LC-MS (MH ⁺ ): 307.

The following compounds can be synthesized in the same way:

a91 1- [2- (2,6-difluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 325 a92 1- [2- (2,3-difluoro-4-methoxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 325

27.4 1- [2- (3-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone Synthesis of a93 .

Anhydrous lithium iodide (1.36 g, 10.18 mmol, 1 eq) was added to 1- [2- (3-fluoro-4-methoxyphenyl) -6,7-dihydro [in 2,6-lutidine (30 ml). 1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl ] ethanone a90 (3.1 g, 10.18 mmol, 1 eq) was added. The mixture was stirred overnight at 125 ° C. under argon atmosphere. The mixture was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted with dichloromethane. The aqueous phase was concentrated under reduced pressure to give a brown solid. This solid was dried over P ₂ O ₅ under reduced pressure to give 3.5 g of crude 1- [2- (3-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5 , 4-c] pyridin-5 (4H) -yl] ethanone a93 was obtained.

Yield: 100%.

LC-MS (MH ⁺ ): 293

The following compounds can be synthesized in the same way:

a94 1- [2- (2,6-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 311 a95 1- [2- (2,3-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 311

27.5 Synthesis of 4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -2-fluorophenyl acetate a96 .

Acetic anhydride (1.9 ml, 20.36 mmol, 2 eq) and 4-dimethylaminopyridine (245 mg, 2 mmol, 0.2 eq) in 1- [2- (3-fluoro-4-hydride in dichloromethane (30 ml) Add to the solution of oxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone a93 (2.98 g, 10.18 mmol, 1 eq) It was. The mixture was stirred at 40 ° C. for 5 hours. The mixture was dissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: dichloromethane / methanol 100: 0 to 0: 100) to give 2.5 g of crude 4- (5-acetyl-4,5,6,7-tetrahydro [ 1,3] thiazolo [5,4-c] pyridin-2-yl) -2-fluorophenyl acetate a96 was obtained.

Yield 40%.

LC-MS (MH ⁺ ): 335.

The following compounds can be synthesized in the same way:

a94 1- [2- (2,6-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 311 a95 1- [2- (2,3-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 311

27.6 1- [2- (3-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone synthesis of a99 .

4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) -2-fluorophenyl acetate in methanol (150 ml) A solution of a96 (2.5 g, 7.48 mmol, 1 eq) was treated with sodium under argon atmosphere and the mixture was stirred at 25 ° C. overnight. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on silica gel (gradient: acetonitrile / water 5:95 to 70:30) to give 0.9 g of 1- [2- (3-fluoro-4-hydroxyphenyl) -6 , 7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone a99 was obtained as a beige solid.

Yield 40%.

LC-MS (MH ⁺ ): 293.

The following compounds can be synthesized in the same way:

a100 1- [2- (2,6-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 311 a101 1- [2- (2,3-difluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] Ethanon LC-MS (MH ⁺ ): 311

27.7 5-acetyl-2- {3-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3 ] Synthesis of thiazolo [5,4-c] pyridine 39 .

1- [2- (3-fluoro-4-hydroxyphenyl) -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (in tetrahydrofuran (50 ml) 4H) -yl ] ethanone a99 (0.9 g, 3.07 mmol, 1 eq) was treated with molecular sieve (600 mg), 15-crown-5 (1.1 ml, 6.14 mmol, 2 eq) under argon atmosphere, The mixture was stirred at 30 ° C. for 30 minutes. Sodium hydride (60% in mineral oil, 246 mg, 6.14 mmol, 2 eq) was added and the mixture was stirred at 60 ° C. for 1 hour. Then cis-3- (piperidin-1-yl) cyclobutyl 4-bromobenzenesulfonate a106 (1.26 g, 3.37 mmol, 1.1 eq) was added and the mixture was heated at 60 ° C. for 12 days. . The mixture was dissolved in water, extracted three times with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on aluminine (gradient: dichloromethane / hexanes 90:10 to 100: 0) to give 60 mg of 5-acetyl-2- {3-fluoro-4-[(trans-3- Piperidine-1 -ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine 39 was obtained as an orange solid.

Yield: 4%.

LC-MS (MH ⁺ ): 430.

Compounds 38 and 40 can be synthesized in the same manner.

Example  28. 4-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -5,6,7,8-te The Lahydro-4H- [1,3] Oxazolo [5,4-b] Azepine  Synthesis of 67.

28.1 Synthesis of N- (2-oxoasepan-3-yl) -4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} benzamide a102

3-amino-azepan-2-one (0.86 g, 6.69 mmol, 3.15 eq), palladium (II) acetate (48 mg, 0.21 mmol, 0.1 eq), molybdenum hexacarbonyl ( 574 mg, 2.18 mmol, 1.024 eq), 1- [trans-3- (4- iodophenoxy ) cyclobutyl] piperidine a68 (0.76 g, 2.12 mmol, 1 eq) and anhydrous tetrahydrofuran (7.5 ml ) This vial was covered with Teflon stopper under argon atmosphere and the mixture was cooled to 0 ° C. using an ice bath. 1,8-diazabicyclo [5.4.0] undec-7-ene (1.1 ml, 7.22 mmol, 3.4 eq) was added via stopper. The vial was stirred at 125 ° C. for 20 minutes under microwave irradiation. After cooling, the reaction mixture was filtered through a short pad of celite and the filtrate was dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 100: 0: 0 to 90: 10: 0.1) to give N- (2-oxoasepan-3-yl) -4- {[Trans-3- (piperidin-1-yl) cyclobutyl] oxy} benzamide a102 was obtained.

Yield: 46%.

LC-MS (MH ⁺ ): 386.

28.2 4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5, 6,7,8-tetrahydro-4H- [1,3] oxa Synthesis of Jolo [5,4-b] azepine 67 .

N- (2-oxo-azpan-3-yl) -4- (3-piperidin-1-yl-cyclobutoxy) -benzamide (0.58 g, 1.5 mmol, 1 eq) in a thick-walled vial ), Acetic anhydride (1.4 ml, 14.81 mmol, 9.8 eq) and titanium tetrachloride (2.2 ml, 19.8 mmol, 13.2 eq) in chloroform (22 ml). The vial was sealed with a Teflon stopper and the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. The mixture was dissolved in dichloromethane (50 ml) and brought to pH 9 by addition of saturated aqueous sodium hydrogen carbonate solution. Solid precipitate was removed by filtration. The organic and aqueous phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to give a brown oil. The residue was purified by flash chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 95: 5: 0.5 to 90: 10: 0.1) to give 0.343 g of 4-acetyl-2- {4-[(trans- 3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6,7,8-tetrahydro-4H- [1,3] oxazolo [5,4-b] azepine 67 was obtained. .

Yield 50%.

LC-MS (MH ⁺ ): 410.

2- {4-[(trans-3-piperidin-1 -ylcyclobutyl) oxy] phenyl} -4- (trifluoroacetyl) -5,6,7,8-tetrahydro-4H- [1 , 3] oxazolo [5,4-b] azepine 68 can be synthesized in the same manner.

Example  29. 2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -3H- Imidazo [4,5-c] pyridine  69, 5-acetyl-2- {4-[( Sheath -3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl} -4,5,6,7- Tetrahydro -3H- Imidazo [4,5-c] pyridine  61 and 5-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7- Tetrahydro -3H- Imidazo [4,5- c] Synthesis of pyridine 62.

29.1 Synthesis of N- (3-aminopyridin-4-yl) -4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} benzamide a103 .

1- [trans in tetrahydrofuran (150 ml) in a vessel sealed with pyridine-3,4-diamine (5.08 g, 46.54 mmol, 3.3 eq), palladium acetate (0.596 g, 2.65 mmol, 0.19 eq) and molecular sieve To a solution of -3- (4- iodophenoxy ) cyclobutyl] piperidine a68 (5.05 g, 14.14 mmol, 1 eq). The mixture was stirred at 70 ° C. under 22 bar of carbon oxide for 54 hours. The mixture was then dissolved in ethyl acetate (300 ml) and washed with water (2 x 100 ml). This was further washed with water at 35 ° C. until the pH of the aqueous phase was 7.5. The organic phase was then washed with brine (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give 2.3 g of crude product. The aqueous phase was also concentrated, dissolved in 60 ml of water, extracted with ethyl acetate (3 × 40 ml), dried over magnesium sulfate and concentrated under reduced pressure to give another 0.4 g of crude product.

2.3 g of crude product of the first was purified by reverse phase chromatography on silica gel (eluent: methanol / water / ammonia 5: 95: 0.1) to give 0.777 g of N- (3-aminopyridin-4-yl) -4 -{[Trans-3- (piperidin-1 -yl ) cyclobutyl] oxy} benzamide a103 was obtained.

Yield: 15%.

LC-MS (MH ⁺ ): 367.

29.2 Synthesis of 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -3H-imidazo [4,5-c] pyridine 69 .

N- (3-aminopyridin-4-yl) -4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} benzamide a103 (0.39 g, 1.06 mmol in butanol (12 ml) , 1 eq) was treated with 37% hydrochloric acid (0.45 ml) in a sealed tube and the mixture was stirred at 120 ° C. under microwave irradiation for 80 minutes. The vessel was washed with water and the aqueous phase was basified with sodium hydroxide pellets to pH 10. The aqueous phase was extracted with ethyl acetate (3 x 25 ml). The organic phase was washed with water, brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (eluent: dichloromethane / methanol / ammonia 87.5: 12.5: 1.25) to give 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) Oxy] phenyl} -3H-imidazo [4,5-c] pyridine 69 was obtained.

Yield: 5%.

LC-MS (MH ⁺ ): 349.

29.3 5-acetyl-2- {4-[( Sheath -3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7-te Tra Hydro-3H- Imidazo [4,5-c] pyridine  61 and 5-acetyl-2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -4,5,6,7- Tetrahydro -3H- Imidazo [4,5-c] pipes Synthesis of Dean 62.

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -3H-imidazo [in acetic acid (100 ml) and palladium dioxide (0.149 g, 0.66 mmol, 0.46 eq) A solution of 4,5-c] pyridine 69 (0.5 g, 1.43 mmol, 1 eq) was treated overnight at 100 ° C. under 75 bar hydrogen. The mixture was filtered over celite and concentrated to dryness. The residue is purified by chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 100: 0: 0 to 85: 15: 1.5) and then reversed phase chromatography (eluent: acetonitrile / water / trifluoroacetic acid) 5: 95: 0.1) to give 5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro- 3H-imidazo [4,5-c] pyridine 62 and 5-acetyl-2- {4-[(cis-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c] pyridine 61 was obtained.

Yield: 17% (Compound 62 ) and 2.5% (Compound 61 ).

LC-MS (MH ⁺ ): 395.

Example  30. 1- {trans-3- [4- (5-acetyl-4,5,6,7- Tetrahydro [1,3] tea Azolo [ 5,4-c] pyridine -2 days) Phenoxy ] Cyclobutyl } -N, N- Dimethylpyrrolidine Synthesis of 3-amine 50.

30.1 Synthesis of cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-bromobenzenesulfonate a104 .

A solution of cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutanol a74 (4.95 g, 26.86 mmol, 1 eq) in ethyl acetate (130 ml) was N-methylimide at 25 ° C. Treated with sol (2.36 ml, 29.55 mmol, 1.1 eq) and 4-bromo-benzenesulfonyl chloride (8.24 g, 32.23 mmol, 1.2 eq). After 4 hours, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: dichloromethane / methanol / ammonia 100: 0: 0 to 90: 10: 0.1) to 3.24 g cis-3- [3- (dimethylamino) pyrroli Din-1-yl] cyclobutyl 4-bromobenzenesulfonate a104 was obtained as a black oil.

Yield: 30%.

LC-MS (MH ⁺ ): 403/405.

Cis-3- (4-cyclopentyl-piperazin-1-yl) cyclobutyl 4-bromobenzene sulfonate a105 (LC-MS (MH ^+): 443/445) may be synthesized in the same manner.

Alternative method : Synthesis of cis-3- (piperidin-1-yl) cyclobutyl 4-bromobenzenesulfonate a106 .

A solution of cis-3-piperidin-1- ylcyclobutanol a17 (310 mg, 2 mmol, 1 eq.) In ethyl acetate (10 ml) was purified with 4-bromobenzenesulfonyl chloride (613 mg, 2.4 mmol, 1.2 eq) and N-methylimidazole (240 μl, 3 mmol, 1.5 eq). The mixture was stirred at rt for 12 h. The reaction mixture was filtered and the precipitate was rinsed with ethyl acetate. The solid was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and saturated ammonium chloride. The organic phase was dried over magnesium sulfate to give 543 mg of cis-3- (piperidin-1-yl) cyclobutyl 4-bromobenzenesulfonate a106 as a yellow oil.

Yield 72%.

LC-MS (MH ⁺ ): 374/376.

30.2 N, N-dimethyl-1- {trans-3- [4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy ] Cyclobutyl} pyrrolidin-3-amine a107 synthesis.

4- (4,5,6,7-tetrahydro-thiazolo [5] in anhydrous tetrahydrofuran (28 ml), 15-crown-5 (5.6 ml, 28.77 mmol, 2 eq) and molecular sieve (20 g) A solution of, 4-c] pyridin-2-yl) -phenol (3.34 g, 14.39 mmol, 1 eq) was stirred at 40 ° C. for 20 minutes. Sodium hydride (60% mineral oil, 1.151 g, 28.77 mmol, 2 eq) was added and the mixture was stirred at 60 ° C. for 2 hours. Then add cis-3- [3- (dimethylamino) pyrrolidin-1-yl] cyclobutyl 4-bromobenzenesulfonate a104 (7 g, 18.7 mmol, 1.3 eq) and mix the mixture overnight at 70 ° C. Stirred. The mixture was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an orange oil. This oil was dissolved in dichloromethane, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 1.68 g of N, N-dimethyl-1- {trans-3- [4- (4,5,6, 7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy] cyclobutyl} pyrrolidin-3-amine a107 was obtained as an orange oil, which was further purified. It was used without.

Yield 53%.

LC-MS (MH ⁺ ): 399.

The following compounds can be synthesized in the same way:

a108 2- (4-{[trans-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine LC-MS (MH ⁺ ): 439 a109 2- (4-{[trans-3- (2-methylpyrrolidin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine LC-MS (MH ⁺ ): 370

30.3 1- {trans-3- [4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy] cyclo Synthesis of Butyl} -N, N-dimethylpyrrolidin-3-amine 50 .

N, N-dimethyl-1- {trans-3- [4- (4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine- in dichloromethane (65 ml) A solution of 2-yl) phenoxy] cyclobutyl} pyrrolidin-3-amine a107 (1.68 g, 4.22 mmol, 1 eq) was added 4-dimethylaminopyridine (86 mg, 0.42 mmol, 0.1 eq) and acetic anhydride ( 0.6 ml, 6.32 mmol, 1.5 eq). The mixture was stirred at 40 ° C. overnight. The mixture was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 860 mg of crude product. This residue was purified by reverse phase chromatography on silica gel (gradient: acetonitrile / water / ammonia 5: 95: 0.1 to 50: 50: 0.1) to give 70 mg of 1- {trans-3- [4- (5 -Acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy] cyclobutyl} -N, N-dimethylpyrrolidine-3 -Amine 50 was obtained as a white sticky solid.

Yield: 4%.

LC-MS (MH ⁺ ): 441.

5-acetyl-2- (4-{[trans-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine 51 and 1- [2- (4-{[trans-3- (2-methylpyrrolidin-1-ylcyclobutyl] oxy} phenyl) -6,7-di Hydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] ethanone a110 (LC-MS (MH ⁺ ): 412) can be synthesized in the same manner.

Compound a110 was separated by chiral chromatography (phase: Chiralpak IA; 30 ° C., column 50 * 500 mm; eluent: ethanol / heptane / diethylamine 50: 50: 0.1) to give 5-acetyl-2- [4- ({Trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] Pyridine, Isomer A 57 and 5-acetyl-2- [4-({trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetra Hydro [1,3] thiazolo [5,4-c] pyridine, isomer B 59 was obtained.

Example  31. 2- {4-[(trans-3-piperidine-1- Monocyclobutyl ) Oxy ] Phenyl } -6,7- Dihi Draw [ 1,3] tee Azolo [4,5-c] pyridine-5 (4H)- Carboxamide  Synthesis of 64.

31.1 2- (4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5 -c] Synthesis of pyridine a111 .

2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} [1,3] thiazolo [4,5-c] pyridine in anhydrous tetrahydrofuran (45 ml) 32 A solution of (915 mg, 2.5 mmol, 1 eq) was treated with a 1M solution of lithium triethyl borohydride in tetrahydrofuran (10.5 ml, 4.2 eq). The mixture was stirred at 20 ° C. for 1 hour. 1 N hydrogen chloride and ethyl acetate were added and the phases were separated. The aqueous phase was brought to pH 9 with solid calcium carbonate and further extracted with ethyl acetate. This last organic phase was dried over magnesium sulfate and concentrated in vacuo to give 399 mg of crude 2- (4-{[trans-3- (piperidin-1-yl) cyclobutyl] oxy} phenyl) -4,5 , 6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine a111 was obtained as a yellow oil which was used without further purification.

Yield 43%.

LC-MS (MH ⁺ ): 370.

31.3 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5-c] pyridine-5 Synthesis of (4H) -carboxamide 64 .

Compound 64 can be obtained as described in Example 3.

LC-MS (MH ⁺ ): 413.

Table 1 below shows the IUPAC name of the compound, the ion peak indicated in the mass spectrometry, ¹ H NMR substrate and melting point.

Table 11. Example  Physical Properties of Compounds

Example  21.Histamine H ₃  Affinity for the receptor; station Efficacy , Antagonism  And efficacy Sex active: [ ³⁵ S] GTP γS-binding assay human histamine H ₃  Receptor.

Substances and Methods

reagent

Analytical grade reagents and reference compounds are available from various commercial sources. [ ³ H] -N-α-methylhistamine (80-85 Ci / mmol) and [ ³⁵ S] -GTPγS (1250 Ci / mmol) were purchased from Perkin Elmer (Belgium). Cell culture reagents were purchased from Cambrex (Belgium).

Test and reference compounds were dissolved in 100% DMSO to give 1 mM stock solution. The final DMSO concentration under assay does not exceed 1%.

CHO cell lines expressing unsliced full-length (445 AA) human H ₃ histamine receptors are described, for example, in Euroscreen S. a. It is available from (Euroscreen SA) (Belgium).

Cell culture

Cells were grown in HAM-F12 medium containing 10% fetal calf serum, 100 IU / ml penicillin, 100 μg / ml streptomycin, 1% sodium pyruvate and 400 μg / ml gentamycin. Cells were maintained at 37 ° C. in a humidified atmosphere consisting of 95% air and 5% CO ₂ .

membrane( membrane ) Produce

The adhered cells were isolated by incubating at 37 ° C. in PBS / EDTA 0.02% for 10 minutes. The cell suspension was centrifuged at 1,500 × g for 10 minutes at 4 ° C. The pellet was homogenized in 15 mM Tris-HCl buffer (pH 7.5) containing ₂ mM MgCl ₂ , 0.3 mM EDTA, 1 mM EGTA (Buffer A). The crude homogenate was lyophilized in liquid nitrogen. DNAse (1 μl / ml) was then added and the homogenates were further incubated at 25 ° C. for 10 minutes, then centrifuged at 40,000 × g for 25 minutes at 4 ° C. The pellet was resuspended in Buffer A and washed once more under the same conditions. The final membrane pellet is resuspended in 7.5 mM Tris-HCl buffer (pH 7.5) rich in 12.5 mM MgCl ₂ , 0.3 mM EDTA, 1 mM EGTA, and 250 mM sucrose, at a protein concentration of 1-3 mg / ml and used. Until stored in liquid nitrogen.

Combine black

[ ³ H] -N-α- Methylhistamine  Combine black

The affinity of the compound for human histamine H ₃ receptor can be assessed by competition with [ ³ H] -N-α-methylhistamine. Such binding assays can be run on any human or non-human H ₃ sequence. Briefly, membranes expressing the human H ₃ histamine receptor (20-40 μg protein) were treated with 2 mM MgCl ₂ , 0.2 nM [ ³ H] -N-α-methyl-histamine, and increasing concentrations of the drug at 25 ° C. Incubation was in 0.5 ml of 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding (NSB) is defined as the remaining binding identified in the presence of 10 μM of thioperamide or histamine. The membrane-bound radioligand and free radioligand were separated by rapid filtration through a glass fiber filter presoaked with 0.1% PEI. Samples and filters were rinsed with at least 6 ml of ice cooled 50 mM Tris-HCl buffer, pH 7.4. The entire filtration process did not exceed 10 seconds per sample. The radioactivity captured onto the filter was counted by liquid scintillation in a β-counter.

[ ³⁵ S]- GTP γS binding assay

Stimulation (agonist) or inhibition (reverse agonist) of [ ³⁵ S] -GTPγS that binds to a membrane expressing a human H ₃ histamine receptor (MoI. Pharmacol. 1993, 44, 1) by Lorenzen et al. The procedure described in 15-123) was measured with slight modifications. In brief, membranes expressing the human H ₃ histamine receptor (10-20 μg protein) were prepared at 25 ° C., containing 3 mM MgCl ₂ , 50 mM NaCl, 1 μm GDP, 2 μg saponin and increasing concentrations of the drug. Incubate in 0.2 ml of mM Tris-HCl buffer, pH 7.4. After 15 minutes of pre-incubation, 0.2 nM of [ ³⁵ S] -GTPγS was added to the sample. Non-specific binding (NSB) is defined as the remaining binding confirmed in the presence of 100 μM Gpp (NH) p. Membrane-bound and free radiation ligands were separated by rapid filtration through glass fiber filters. Samples and filters were rinsed with at least 6 ml, ice cooled 50 mM Tris-HCl buffer, pH 7.4. The entire filtration process did not exceed 10 seconds per sample. The radioactivity captured onto the filter was counted by liquid scintillation in a β-counter.

Data Analysis

Measurement of plC ₅₀ / pKi / pEC ₅₀ / pEC ₅₀ INV

analysis

The raw data were analyzed by nonlinear regression using XLfit ^™ (UK, IDBS) according to the following general equation.

B = MIN  + [( MAX  - MIN ) / (1 + (((10 ^x ) / (10 ^{- pX50} )) ^nH ))]

In the above equation,

B is a radioligand (dpm) bound in the presence of an unlabeled compound,

MIN is the minimum binding identified (dpm),

MAX is the maximum combined match (dpm),

X is the concentration of unlabeled compound (log M),

pX ₅₀ (-log M) is the concentration of unlabeled compound that causes 50% of the maximal effect (inhibition or stimulation of the binding radioligand). This indicates plC ₅₀ when measuring the affinity of the compound for receptors in binding studies with [ ³ H] -N-α-methylhistamine, a compound that stimulates the binding of [ ³⁵ S] -GTPγS (agonist) For pEC ₅₀ , for compounds that inhibit the binding of [ ³⁵ S] -GTPγS (reverse agonist) pEC ₅₀ INV,

n _H is the heel coefficient,

pKi can be obtained by applying the following equation (Cheng and Prusoff, 1973, Biochem. Pharmacol., 22: 3099-3108):

pKi  = plC ₅₀  + log  (1 + L / Kd )

In the above equation,

pKi is the unlabeled compound equilibrium dissociation constant (-log M),

L is the radioligand concentration (nM),

Kd is the radiation ligand equilibrium dissociation constant (nM).

Compounds of formula (I) according to the invention exhibited a pIC ₅₀ value of at least 6.5, preferably greater than 7.5, for the histamine H ₃ receptor.

Compounds of formula (I) according to the invention exhibited pEC ₅₀ INV values typically greater than 7.5 for the histamine H ₃ receptor.

Example  22. Antagonist activity: Paced ( paced ) Separated Guinea pig Muscle layer  Electric field stimulation assay.

Substances and Methods

reagent

Stock solutions (10 ⁻² M) and further dilutions of the compounds to be tested were freshly prepared in DMSO (WNR, Ruben, Belgium). All other reagents (components of R (-)-α-methylhistamine, mepyramine, ranitidine, propranolol, yohimbine and Krebs solution) were of analytical grade and they were obtained from all conventional commercial sources.

animal

Four-week-old male Dunkin-Hartley guinea pigs (200-300 g) were supplied from the Charles River (Saltfeld, Germany). All animals were arranged and used under the protocol "orgisol-GP" approved by the UCB Pharma ethical committee. Groups of 12 animals were housed in stainless steel cages (75 × 50 × 30 cm) in a UCB animal facility and acclimatise for at least 1 week prior to inclusion in this experiment. Room temperature was maintained at 20-24 ° C., and 40-70% relative humidity. A 12 hour contrast cycle was applied. Animals had free access to food and water.

Organ preparation

This method has been modified from the method described by Menkveld et al. (Eur. J. Pharmacol. 1990, 186, 343-347). It was prepared from the guinea pig ileum isolated from the longitudinal muscle layer plexus. The tissue was placed in 10 ^-7 M mepi Ramin, 10 ^-5 M ranitidine, 10 ^-5 M propranolol and 10 ^-6 M yohimbine 20 ml long term storage tank (organ bath) for containing a modified Krebs solution which contains a. The solution in the reservoir was maintained at 37 ° C. and gasified with 95% O ₂ to 5% CO ₂ . The tissues were equilibrated for a period of 60 minutes under 0.5 g resting tension and electric field stimulation (5-20 V, 1 ms and 0.1 Hz pulses were applied during the previous experiment). The stimulus induced a contractile contraction that was stable and regenerated. Isomeric contractions may be applied to (i) automatic data acquisition, (ii) bath cleaning by automatic fluid circulation through an electric valve at a predetermined time or signal stability, and (iii) Measurements were made by a force-displacement transducer connected to an amplifier connected to a computer system (EMKA Technologies) that can control automatic dilution / infusion.

protocol

After a 60 minute stabilization period, tissues were stimulated twice with 10 ⁻⁶ MR (−)-α-methylhistamine at 30 minute intervals. After a 60 minute incubation period in the presence of a solvent or antagonist test compound, an accumulation concentration-response to R (-)-α-methylhistamine was induced (10 ^-10 to 10 ^-4 M). Only one concentration of antagonist was tested for each tissue.

Data Analysis

Proper estimation of the interaction between agonists and antagonists can be made by studying the curve families identified in the presence or absence of increasing antagonist concentrations. The values of each relevant parameter (pD ₂ and E _max ) of each concentration-response curve are obtained from repetitive computer software (XLif, IDBS, Wexford, UK) that fits the experimental data into a four-parameter logical equation. Was calculated by. The antagonist activity of the test substance is described by Van Rossum et al. By the methods described in Arch. Int. Pharmacodyn. Ther. 1963, 143, 299 and / or by Arunlakshana & Schild. Estimated by calculating pD ' ₂ and / or pA ₂ values according to the method described in (Br. J. Pharmacol 1959, 14, 48).

Results are expressed as mean ± SD. The number of confirmations is indicated by n.

Compounds of formula (I) according to the invention typically exhibited pA ₂ values of at least 7.5 for the histamine H ₃ receptor.

Example  23. hERG  Research

This is a test compound for human ether-a-go-go-related gene (hERG) -encoded channel tail currents recorded from HEK293 cells stably transfected with hERG cDNA. In vitro electrophysiological patch clamp studies to assess potential effects. Coverslips with cells seeded thereon were mounted in the recording chamber and fused with physiological saline. Recording of the tail current was done in voltage patch clamp mode. A reference material, for example E-4031, was used to confirm that the identified current could be inhibited by known hERG channel blockers (Zhou, Z. et al., Biophys. J., 1998, 74, 230-241). .

Compounds of the invention typically exhibited weak hERG channel affinity. In general, the hERG channel affinity of the compounds of formula (I) is at least 1 μM.

Example  24. The brain H ₃ Receptor occupancy

Substances and Methods

reagent

[ ³ H] -N-α-methylhistamine (80-85 Ci / mmol) was purchased from Perkin Elmer (Belgium). Reagents and reference compounds used in binding assays for cerebral cortical tissue were of analytical grade and obtained from various commercial sources. Reference compound was dissolved in 100% dimethylsulfoxide (DMSO) to give a 1 mM stock solution. Final DMSO concentration in the assay did not exceed 1%.

Animals and processing

The experimental procedures involving animals were conducted in accordance with the regulations of the Regional Institutional Review Board for Animal Testing under Belgian law. Young male SPFs (Sprague-Dawley rats) weighing 200-300 g (OFA lineage, supplied by Belgium IFFA CREDO) were used. I.p. Vehicle or test compound was administered by the route of administration. The compound was dissolved in both a mixture of 1% methyl cellulose (MC) and 5% DMSO. A dose volume of 5 mg / kg body weight was used. The control group was administered the same dose volume of MC 1% / DMSO 5%. Animals were killed 1 or 3 hours later. Peripheral blood samples were collected and brains were quickly removed. Brain cortex was dissected on ice at 4 ° C.

Just ready

 Brain cortical tissue was rapidly homogenized in 2.5 volumes of ice cooled buffer containing 50 mM Tris-HCl and 250 mM sucrose, pH 7.4. Homogenates were frozen in liquid nitrogen and stored at −80 ° C. until use.

[ ³ H] -N-α-methylhistamine binding assay

[ ³ H] -N-α-methylhistamine binding assay was performed in 50 mM Tris-HCl buffer (pH 7.4) containing 2 mM MgCl ₂ . Briefly, homogenates were frozen and incubated for 15 minutes at room temperature before use. Homogenates (500 μg of protein) were incubated in 0.2 ml buffer and 0.2 nM [ ³ H] -N-α-methylhistamine at 25 ° C. for 5 minutes. Nonspecific binding (NSB) is defined as the remaining binding identified in the presence of 10 μm thioperamide. Membrane-bound radioligands and free radioligands were separated by rapid filtration through glass fiber filters (GF / C) (pre-soaked in 0.1% PEI). Samples and filters were rinsed with 8 ml of ice-cold 50 mM Tris-HCl buffer, pH 7.4. The entire filtration process did not exceed 10 seconds per sample. The radioactivity captured onto the filter was counted by liquid scintillation in a β-counter. Protein concentration was measured using the BCA Pierce method using bovine serum albumin as standard.

Data Analysis

The percent receptor occupancy is defined according to the following formula:

1-((B- NSB ) (Treated animals) / (B- NSB ) (Control)) * 100

Wherein B is bound radioligand (dpm) and NSB is nonspecific binding.

IC ₅₀ values (capacity required to represent a 50% reduction in in vitro radioligand binding) were determined using non-measurement using GraphPad Prism 4 software (San Diego GraphPad, Inc.) according to the following general equation: Determined by plotting and analyzing log ₁₀ of the ip dose for% specific binding by linear regression:

Y = MIN + (MAX-MIN) / (1 + 10 ^{( LogIC50 -X) * nH} )

Where Y is the response, X is the logarithmic value of concentration, MIN is the minimum binding (dpm) identified, MAX is the maximum binding (dpm) identified, and n _H is the Hill coefficient.

Compounds of formula (I) according to the invention typically exhibit a receptor occupancy of at least 70% at a 1 mg / kg ip dose.

Claims (17)

A compound of formula (I), its geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, and all possible mixtures thereof:

Where
A is a substituted or unsubstituted aliphatic or cyclic amino group linked to a cyclobutyl group via amino nitrogen;
A ¹ is CH, C-halogen or N;
B is selected from the group consisting of heteroaryl, 5-8 membered heterocycloalkyl and 5-8 membered cycloalkyl;
X is O, S, NH or N (C _{1 -4} alkyl);
Y is O, S or NH;
R ¹ is sulfonyl, amino, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} aryl, heteroaryl, C _{3 -8} cycloalkyl, 3- to 8-membered heterocycloalkyl, acyl, C _{1 -6} alkyl, aryl, C _{1 -6-alkyl-heteroaryl,} C _{2 -6} alkenyl, aryl, C _{2 -6} alkenyl, heteroaryl, C _{2 -6-alkynyl} aryl, C _{2 -6-alkynyl} heteroaryl, C _1-6 alkylcycloalkyl, C _1-6 alkyl, heterocycloalkyl, C _{2 -6} alkenyl, cycloalkyl, C _{2 -6} alkenyl heterocycloalkyl, C _{2 -6-alkynyl} cycloalkyl, C _{2 -6-alkynyl} heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C _{1 -6} alkyl, carboxy, C _{1 -6} alkyl, acyl, aryl acyl, heteroaryl acyl, C _{3 -8} (hetero) cycloalkyl acyl, C _{1 -6} alkyl, acyl oxy, C _-6 alkyl, alkoxy, C _-6 alkyl alkoxycarbonyl, C _-6 alkylamino-carbonyl, C _{1 -6-alkyl} acylamino, acylamino, acyl-aminocarbonyl, ureido, C _{1 -6} alkyl ureido , C _{1 -6} Kill carbamate, C _{1 -6} alkylamino, C _{1 -6} alkylsulfonyloxy, C _{1 -6} alkyl sulfonyl, C _{1 -6} alkyl sulfinyl, C _{1 -6-alkyl} sulfanyl, C _{1 -6} alkyl sulfonylamino, aminosulfonyl, C _{1 -6-alkyl} aminosulfonyl, hydroxy, C _{1 -6} alkyl, hydroxy, phosphonate, C _{1 -6} alkyl phosphonate, C _{1 -6} alkyl phosphono, halogen , Cyano, carboxy, oxo, thioxo, or selected from the group consisting of these;
n is 0, 1, 2 or 3;
R ² is hydrogen, sulfonyl, amino, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} aryl, heteroaryl, C _{3 -8} cycloalkyl, 3- to 8-membered heterocycloalkyl, acyl, C _{1 -6} alkyl, aryl, C _{1 -6-alkyl-heteroaryl,} C _{2 -6} alkenyl, aryl, C _{2 -6} alkenyl, heteroaryl, C _{2 -6-alkynyl} aryl, C _{2 -6-alkynyl} heteroaryl , C _{1 -6} alkyl, cycloalkyl, C _{1 -6} alkyl, heterocycloalkyl, C _{2 -6} alkenyl, cycloalkyl, C _{2 -6} alkenyl heterocycloalkyl, C _{2 -6-alkynyl} cycloalkyl, C _{2 -6} alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C _{1 -6} alkyl, carboxy, C _{1 -6} alkyl, acyl, aryl acyl, heteroaryl acyl, C _{3 -8} - (hetero) cycloalkyl acyl, C _{1 - 6-alkyl} acyloxy, C _{1 -6} alkyl, alkoxy, C _{1 -6-alkyl} alkoxycarbonyl, C _{1 -6} alkylamino-carbonyl, C _{1 -6-alkyl} acylamino, acylamino, acyl-aminocarbonyl, ureido, C _{1 -6} alkyl urea FIG, C _1-6 alkyl carbamate, C _{1 -6} alkylamino, C _{1 -6} alkylsulfonyloxy, C _{1 -6} alkyl sulfonyl, C _1-6 alkyl sulfinyl, C _{1 -6} alkyl sulfanyl , C _{1 -6-alkyl} sulfonylamino, aminosulfonyl, C _{1 -6-alkyl} aminosulfonyl, hydroxy, C _{1 -6} alkyl, hydroxy, phosphonate, C _{1 -6} alkyl phosphonate, C _{1 - 6} alkyl phosphono, halogen, cyano, carboxy, oxo, thioxo, or selected from the group consisting of these;
m is 0 or 1;
R ³ is hydrogen, C _{1 -6} alkyl, halogen or C _{1 -6} alkoxy. 2. Compounds according to claim 1, wherein A ¹ is CH, CF or N. The compound of claim 1 or 2, wherein n is zero. Any one of claims 1 to A method according to any one of claim 3, wherein, R ² is hydrogen, carboxy, acyl, substituted or unsubstituted C _{3 -8} cycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, alkoxy carbonyl, aminocarbonyl, optionally substituted C _{1 -6} alkyl, aminocarbonyl, aminosulfonyl, optionally substituted C _{1 -6} alkyl, hydroxy, optionally substituted C _{1 -6} alkyl phosphonium And a substituted or unsubstituted C _1-6 alkyl phosphono. The compound of any one of claims 1-4 where X is O. 6. The compound of any one of claims 1-5, wherein A is a 3-8 membered heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom. The substituted or unsubstituted piperidin-1-yl, substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted pyrrolidine-A according to any one of claims 1 to 6. Selected from the group comprising or consisting of 1-yl, substituted or unsubstituted piperazin-1-yl, substituted or unsubstituted azepan-1-yl, or substituted or unsubstituted thiomorpholin-4-yl , A 3-8 membered heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom. 8. The substituted or unsubstituted according to claim 1, wherein B is selected from the group comprising or consisting of tetrahydropyridyl, tetrahydro-1H-azinyl, cyclopentenyl, or pyridyl. Unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl. 9. The process of claim 1, wherein B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted Heteroaryl, B is 4,5,6,7-tetrahydro [1,3] thiazolopyridine, 4,5,6,7-tetrahydro [1, together with an oxazole, thiazole or imidazole ring , 3] thiazolo [4,5-b] pyridine, 4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine, 4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine, 4,5,6,7-tetrahydro-3H-imidazo [4,5-c] pyridine, 5,6,7,8-tetrahydro -4H- [1,3] thiazolo [5,4-b] azepine, 5,6,7,8-tetrahydro-4H- [1,3] oxazolo [5,4-b] azepine, 5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole, 3H-imidazo [4,5-c] pyridine and [1,3] thiazolo [4,5-c] pyridine A compound that forms a fused heterocycle selected from the group consisting of. A compound according to claim 1, represented by the formula (If):

Where
A is a 3-8 membered heterocycloalkyl linked to a cyclobutyl group via a nitrogen atom;
A ¹ is CH;
Y is O, S or NH;
B is substituted or unsubstituted 5, 6 or 7 membered cycloalkyl, substituted or unsubstituted, selected from the group comprising or consisting of tetrahydropyridyl, tetrahydro-1H-azinyl, cyclopentenyl or pyridyl Unsubstituted 5, 6 or 7 membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;
R ² is hydrogen, carboxy, acyl, optionally substituted C _{3 -8} cycloalkyl, alkoxycarbonyl, optionally substituted C _{1 -6} alkyl, non-alkoxycarbonyl, aminocarbonyl, optionally substituted C _{1 -6-alkyl-aminocarbonyl,} aminosulfonyl, optionally substituted C _{1 -6} alkyl, hydroxy, optionally substituted C _{1 -6} alkyl phosphonate, and optionally substituted C _{1 -6} alkyl phosphonium Is selected from the group consisting of phono;
m is 0 or 1;
R ³ is hydrogen or halogen. The compound of claim 1, wherein A is piperidin-1-yl, 2-methylpyrrolidin-1-yl, (2S) -2-methylpyrrolidin-1-yl or (2R) -2-methylpyrrolidin-1-yl. The compound of any one of claims 1-11, wherein Y is S. 12. 13. The compound of any one of claims 1 to 12, wherein R ² comprises or consists of acetyl, aminocarbonyl, hydroxyacetyl, 2-amino-2-oxoethyltyl and amino (oxo) acetyl. Compound selected. The method according to any one of claims 1 to 13,
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6-dihydro-4H-cyclopenta [d] [1,3] thiazole-5- Carboxylic acid;
5- (methoxyacetyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thia Zolo [5,4-c] pyridine;
Tert-butyl 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridine-5 (4H) -carboxylate;
5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] Pyridine;
5- (morpholin-4-ylcarbonyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [ 1,3] thiazolo [5,4-c] pyridine;
5- (morpholin-4-ylsulfonyl) -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1 , 3] thiazolo [5,4-c] pyridine;
5-acetyl-2- {4-[(trans-3-morpholin-4-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4 -c] pyridine;
2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] ethanamine;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 ( 4H) -carboxamide;
2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] ethanol;
5-acetyl-2- (4-{[trans-3- (4-isopropylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine;
5-acetyl-2- (4-{[trans-3- (4,4-difluoropiperidin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [ 1,3] thiazolo [5,4-c] pyridine;
5-acetyl-2- {4-[(trans-3-pyrrolidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;
3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] propane-1,2-diol;
(2S) -3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propane-1,2-diol;
(2R) -3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propane-1,2-diol;
2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] acetamide;
5-acetyl-2- {4-[(trans-3-azane-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4 -c] pyridine;
(3R) -1- {trans-3- [4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy Cy] cyclobutyl} -N, N-dimethylpyrrolidin-3-amine;
N-ethyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridine-5 (4H) -carboxamide;
5-acetyl-2- {4-[(trans-3-thiomorpholin-4-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;
5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) thio] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5, 4-c] pyridine;
Cis-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c ] Pyridin-5 (4H) -yl] cyclobutanol;
3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propanamide;
Methyl [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine- 5 (4H) -yl] acetate;
Diethyl {[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] methyl} phosphonate;
5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] oxazolo [4, 5-c] pyridine;
5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4, 5-c] pyridine;
4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [4, 5-b] pyridine;
4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6,7,8-tetrahydro-4H- [1,3] thiazolo [5,4-b] azepine;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} [1,3] thiazolo [4,5-c] pyridine;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5- (3,3,3-trifluoropropanoyl) -4,5,6,7 Tetrahydro [1,3] thiazolo [5,4-c] pyridine;
{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine- 5 (4H) -yl] methyl} phosphonic acid;
5-[(5-methyl-2H-1,2,3-triazol-4-yl) carbonyl] -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] Phenyl} -4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;
5-acetyl-2- {2-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4.5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;
2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] ethanol;
5-acetyl-2- {2,6-difluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4,5,6,7-tetrahydro [1 , 3] thiazolo [5,4-c] pyridine;
5-acetyl-2- {3-fluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4.5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;
5-acetyl-2- {2,3-difluoro-4-[(trans-3-piperidin-1-ylcyclobutyl) oxy) phenyl} -4,5,6,7-tetrahydro [1 , 3] thiazolo [5,4-c] pyridine;
5- [4- (1-oxydothiomorpholin-4-yl) butanoyl] -2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4, 5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine;
N- {3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [ 5,4-c] pyridin-5 (4H) -yl] propyl} acetamide;
{2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, 4-c] pyridin-5 (4H) -yl] ethoxy} acetic acid;
1,1,1-trifluoro-3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [ 1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propan-2-ol;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5- (tetrahydro-2H-pyran-4-ylcarbonyl) -4,5,6,7 Tetrahydro [1,3] thiazolo [5,4-c] pyridine;
1-{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] carbonyl} cyclopropanol;
1-{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] carbonyl} cyclopropanecarboxamide;
1-{[2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] Pyridin-5 (4H) -yl] carbonyl} cyclopropanecarboxamide trifluoroacetate;
Ethyl oxo [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridine -5 (4H) -yl] acetate;
1- {trans-3- [4- (5-acetyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) phenoxy] cyclobutyl } -N, N-dimethylpyrrolidin-3-amine;
5-acetyl-2- (4-{[trans-3- (4-cyclopentylpiperazin-1-yl) cyclobutyl] oxy} phenyl) -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine;
1- {2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [ 5,4-c] pyridin-5 (4H) -yl] ethyl} urea;
2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] acetamide;
3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] propane-1,2-diol;
3-hydroxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5, 4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione;
3-isopropoxy-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5 , 4-c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione;
5-acetyl-2- [4-({trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine, isomer A;
3-amino-4- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4 -c] pyridin-5 (4H) -yl] cyclobut-3-ene-1,2-dione. 1/2 trifluoroacetate;
5-acetyl-2- [4-({trans-3- [2-methylpyrrolidin-1-yl] cyclobutyl} oxy) phenyl] -4,5,6,7-tetrahydro [1,3] Thiazolo [5,4-c] pyridine, isomer B;
(2S) -3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [5,4-c] pyridin-5 (4H) -yl] propane-1,2-diol;
5-acetyl-2- {4-[(cis-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro-3H-imidazo [4,5- c] pyridine;
5-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4,5,6,7-tetrahydro-3H-imidazo [4,5- c] pyridine;
2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5 -c] pyridin-5 (4H) -yl] ethanol;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5-c] pyridine-5 ( 4H) -carboxamide;
3-oxo-3- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5 -c] pyridin-5 (4H) -yl] propanamide;
2-oxo-2- [2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -6,7-dihydro [1,3] thiazolo [4,5 -b] pyridin-4 (5H) -yl] ethanol;
4-acetyl-2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -5,6,7,8-tetrahydro-4H- [1,3] oxazolo [5,4-b] azepine;
2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -4- (trifluoroacetyl) -5,6,7,8-tetrahydro-4H- [1 , 3] oxazolo [5,4-b] azepine; And
A compound selected from the group consisting of 2- {4-[(trans-3-piperidin-1-ylcyclobutyl) oxy] phenyl} -3H-imidazo [4,5-c] pyridine. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. A compound according to claim 1, or a pharmaceutical composition according to claim 15, for use as a medicament. Mild cognitive impairment, Alzheimer's disease, learning and memory disorders, attention deficit hyperactivity disorder, Parkinson's disease, schizophrenia, dementia, depression, epilepsy, seizures, convulsions, sleep / wake disorders, cognitive dysfunction, narcolepsy, hypersomnia, The method according to any one of claims 1 to 14, which is used for the treatment or prevention of obesity, upper airway allergic disorders, Down syndrome, anxiety, stress, cardiovascular disorders, inflammation, pain disorders, in particular neuropathic pain or multiple sclerosis. Or a pharmaceutical composition according to claim 15.